Tertiary syphilis usually occurs 1–10 years after the initial infection, however in some cases it can take up to 50 years. This stage is characterized by the formation of gummas, which are soft, tumor-like balls of inflammation known as granulomas. The granulomas are chronic and represent an inability of the immune system to completely clear the organism. They may appear almost anywhere in the body including in the skeleton. The gummas produce a chronic inflammatory state in the body with mass effects upon the local anatomy. Other characteristics of untreated tertiary syphilis include neuropathic joint disease, which is a degeneration of joint surfaces resulting from loss of sensation and fine position sense (proprioception). The more severe manifestations include neurosyphilis and cardiovascular syphilis. In a study of untreated syphilis, 10% of patients developed cardiovascular syphilis, 16% had gumma formation and 7% had neurosyphilis.Neurological complications at this stage can be diverse. In some patients manifestations include generalized paresis of the insane, which results in personality changes, changes in emotional affect, hyperactive reflexes and Argyll-Robertson pupil. This is a diagnostic sign in which the small and irregular pupils constrict in response to focusing the eyes, but not to light. Tabes dorsalis, also known as locomotor ataxia, a disorder of the spinal cord, often results in a characteristic shuffling gait. See below for more information about neurosyphilis.Cardiovascular complications include syphilitic aortitis, aortic aneurysm, aneurysm of sinus of Valsalva and aortic regurgitation. Syphilis infects the ascending aorta causing aortic dilation and aortic regurgitation. This can be heard with a stethoscope as a heart murmur. Contraction of the tunica intima leads to a tree bark appearance that is wrinkly. The aortic valve dilation and subsequent insufficiency leads to diastolic regurgitation and causes massive hypertrophy of the left ventricle. The heart grows so large (over 1,000 grams) that the heart is termed cor bovinum (cow's heart). The course can be insidious and heart failure may be the presenting sign after years of disease. The infection can also occur in the coronary arteries and cause narrowing of the vessels. Syphilitic aortitis can cause de Musset's sign, a characteristic bobbing of the head in synchrony with the heartbeat. The clinical course of these cardiovascular effects causes mediastinal encroachment and secondary respiratory difficulties (dyspnea), difficulty swallowing (dyphagia) and persistent cough because of pressure on the recurrent laryngeal nerve triggering the cough reflex. Pain can stem from erosion of the ribs or vertebrae. Also, the cor bovinum can lead to coronary ostia obstruction and ischemia. The aneurysm developed during the disease course may also rupture, leading to massive intrathoracic hemorrhage and likely death; although the most likely cause of death is the heart failure resulting from aortic regurgitation.

Model of the head of a patient with tertiary syphilis.

Latent syphilis is defined as having serologic proof of infection without signs or symptoms of disease.  Latent syphilis is further described as either early or late. Early latent syphilis is defined as having syphilis for two years or less from the time of initial infection without signs or symptoms of disease. Late latent syphilis is infection for greater than two years but without clinical evidence of disease. The distinction is important for both therapy and risk for transmission. In the real world, the timing of infection is often not known and should be presumed to be late for the purpose of therapy. Early latent syphilis may be treated with a single intramuscular injection of a long-acting penicillin. Late latent syphilis requires three weekly injections. For infectiousness late latent syphilis is not considered as contagious as early latent syphilis. Fifty percent of those infected with latent syphilis will progress into late stage (tertiary) syphilis, 25% will stay in the latent stage, and 25% will make a full recovery.

Secondary syphilis occurs approximately 1–6 months (commonly 6 to 8 weeks) after the primary infection. There are many different manifestations of secondary disease. There may be a symmetrical reddish-pink non-itchy rash on the trunk and extremities.  The rash can involve the palms of the hands and the soles of the feet. In moist areas of 
the body (usually vulva or scrotum), the rash becomes flat, broad, whitish, wart-like lesions known as condyloma latum. Mucous patches may also appear on the genitals or in the mouth. All of these lesions are infectious and harbor active treponeme organisms. A patient with syphilis is most
 contagious when he or she has secondary syphilis. Other symptoms common at this stage include fever, sore throat, malaise, weight loss, headache, meningismus and enlarged lymph nodes. Rare manifestations include an acute meningitis  that occurs in about 2% of patients, hepatitis, renal disease, hypertrophic gastritis, patchy proctitis, ulcerative colitis, rectosigmoid  mass, arthritis, periostitis, optic neuritis, interstitial keratitis, iritis and uveitis.


 Typical presentation of secondary syphilis rash on the palms of the hands and usually also seen on soles of feet.

Primary syphilis is typically acquired via direct sexual contact with the infectious lesions of a person with syphilis.  Approximately 10–90 days after the initial exposure (average 21 days) a skin lesion appears at the point of contact, which is usually the genitalia, but can be anywhere on the body. This lesion, called a chancre, is a firm, painless skin ulceration localized at the point of initial exposure to the spirochete, often on the penis, vagina  or rectum. In rare circumstances, there may be multiple lesions present, although it is typical that only one lesion is seen. The lesion may persist for 4 to 6 weeks and usually heals spontaneously. Local lymph node swelling can occur. During the initial incubation period, individuals are otherwise asymptomatic. As a result, many patients do not seek medical care immediately.

Primary chancre  of syphilis on the hand. Unlike some kinds of sexually transmitted infections, syphilis infections are not limited to the genitals, and can be transmitted through non-sexual contact.