Traditionally, case-control studies of sexually transmitted infections and prostate cancer have focused on gonorrhea and syphilis, with overall positive associations. More recently, researchers have begun to expand their focus to include additional sexually transmitted infections, such as Chlamydia trachomatis, human papillomavirus (HPV), and human herpesvirus type 8 (HHV-8) infections. Continuing this investigation, weexamined each of these infections in relation to incident prostate cancer in a nested case-control study within the Health Professionals Follow-up Study. Prostate cancer cases were men diagnosed with prostate cancer between the date of blood draw (1993-1995) and 2000 (n = 691). Controls were men free of cancer and alive at the time of case diagnosis who had had at least one prostate-specific antigen test between the date of blood draw and case diagnosis. One control was individually matched to each case by age; year, time of day, and season of blood draw; and prostate-specific antigen screening history before blood draw (n = 691). C. trachomatis and HPV-16, HPV-18, and HPV-33 antibody serostatus were assessed by enzyme-based immunoassays and HHV-8 antibody serostatus was assessed by an immunofluorescence assay. No associations were observed between C. trachomatis [odds ratio (OR), 1.13; 95% confidence interval (95% CI), 0.65-1.96], HPV-16 (OR, 0.83; 95% CI, 0.57-1.23), HPV-18 (OR, 1.04; 95% CI, 0.66-1.64), and HPV-33 (OR, 1.14; 95% CI, 0.76-1.72) antibody seropositivity and prostate cancer. A significant inverse association was observed between HHV-8 antibody seropositivity and prostate cancer (OR, 0.70; 95% CI, 0.52-0.95). As this study is the first, to our knowledge, to observe such an inverse association, similar additional studies are warranted.