Human papillomavirus (HPV) subtypes 16 and 18 are sexually transmitted and have been associated with an increased incidence of several anogenital tumors. Although previous epidemiological studies have suggested that sexual behaviors such as an early age at first intercourse and larger numbers of sexual partners are also related to an increased risk of prostate cancer, seroepidemiological studies of these infectious agents in relation to prostate cancer have produced differing results. To further evaluate this potential relationship, we completed a population-based control study in King County, Washington. Middle-aged (40-64 years) men diagnosed with prostate cancer (n = 642) were ascertained through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry between January 1993 and December 1996. Controls (n = 570) of similar age were selected from the same population as the cases by random digit dialing. Overall, there was no association between serological evidence of prior HPV-16 (adjusted odds ratio, 1.06; 95% confidence interval, 0.71-1.57) or HPV-18 (adjusted odds ratio, 1.36; 95% confidence interval, 0.69-2.69) infection and the risk of prostate cancer. Analyses of clinical features demonstrated no relationship between HPV infection status and Gleason score, stage of disease, or a combined measure of disease aggressiveness. Our findings indicate that HPV-16 and HPV-18 are not associated with prostate cancer risk.