The dramatic and apparently curative effect of penicillin for the treatment of acute syphilis led to follow-up studies for only comparatively brief periods, and the acceptance of the long-term benefit of penicillin has rested on uncontrolled clinical impressions. More certainty about the efficacy of penicillin was sought by a follow-up review of 251 patients treated between March 1944 and December 1950 under the Penicillin Study of the Office of Scientific Research and Development (OSRD) and continued under U. S. Public Health Service after World War II. Eighty-eight patients were interviewed and examined. Telephone conversation or correspondence was had with 43 subjects; an additional nine are known to be living but did not respond to letters. Thirty-two patients died greater than or equal to 20 years after treatment, and 21 patients died within less than 20 years of treatment. Fifty-eight patients could not be found. Treatment failures were documented. Syphilis was not shown to be the cause of disability or death, except for a patient with meningovascular syphilis who died soon after initial treatment. Disabilities recorded and deaths documented revealed only diseases common to any middle-aged population. The outcomes of 17 pregnancies of women treated for acute syphilis were documented. Blood samples obtained from the 88 subjects examined were tested at the Center for Disease Control (Atlanta, Ga.); the results are recorded and discussed. Methods for locating the patients are described, and the psychosocial findings for the 88 patients interviewed are presented. The study has confirmed the clinical impressions of the therapeutic effectiveness of penicillin, which have been accepted for greater than 30 years.