BACKGROUND:Although previous case-control studies have observed positive associations among gonorrhea, syphilis, clinical prostatitis, and prostate cancer, many may have been susceptible to recall and interviewer biases due to their retrospective designs. Therefore, to investigate these associations without concerns of recall and interviewer biases, we conducted a large, prospective investigation in the Health Professionals Follow-up Study. METHODS:In 1992, participants were asked to report their histories of gonorrhea, syphilis, and clinical prostatitis by mailed questionnaire. Prostate cancer diagnoses were ascertained by self-report on the 1994 and each subsequent biennial follow-up questionnaire and confirmed by medical record review. RESULTS:Of the 36,033 participants in this analysis, 2,263 were diagnosed with prostate cancer between the date of return of the 1992 questionnaire and 2002. No association was observed between gonorrhea [adjusted relative risk (RR), 1.04; 95% confidence interval (95% CI), 0.79-1.36] or syphilis (RR, 1.06; 95% CI, 0.44-2.59) and prostate cancer. Overall null results were also observed between clinical prostatitis and prostate cancer (RR, 1.08; 95% CI, 0.96-1.20), although a significant positive association was observed among younger men (<59 years) screened for prostate cancer (RR, 1.49; 95% CI, 1.08-2.06; P(interaction) = 0.006). CONCLUSIONS:Gonorrhea and syphilis do not seem to be risk factors for prostate cancer in this cohort of men with a lower burden of sexually transmitted infections. Clinical prostatitis is also unlikely to be a risk factor, although possible roles for prostatitis in younger men and asymptomatic prostatic infection and inflammation cannot be ruled out.