Some epidemiological studies of prostate cancer have suggested the existence of a sexually transmitted risk factor, and some studies have reported the presence of human papillomavirus (HPV) DNA in prostate-cancer tissue. To perform a sero-epidemiological evaluation of whether HPV infection is associated with increased risk for prostate cancer, we performed a nested case-control study within a serum bank containing samples from 20,243 healthy Finnish men. We identified 165 cases of prostate cancer that were diagnosed up to 24 years after donation of the serum sample. Two control subjects per case were selected, matched for gender, age and municipality of residence. Serum samples were analyzed for the presence of IgG antibodies against 4 HPV types and against Chlamydia. The presence of antibodies against HPV type 18 was associated with a 2.6-fold increased risk of developing prostate cancer during follow-up (p < 0.005). HPV type 16 tended to be associated with subsequent prostate-cancer occurrence (relative risk: 2.4, p = 0.06), whereas seropositivity for HPV type 11 or type 33 or for Chlamydia was not associated with risk. The results suggest that infection with oncogenic HPV might be involved in the etiology of a minority of prostate cancers.