Biological behavior of male genital human papillomavirus (HPV) infection is incompletely understood, and the clinical value of treatment is obscure. To evaluate the clinical course and possible prognostic factors of genital HPV infections in men. A total of 318 consecutive high-risk men for HPV infection (94.3% partners of HPV-infected women) were examined using peniscopy, histology, cytology, and in situ hybridization (ISH). Only the men with exophytic warts or clinical symptoms were treated, if they insisted on it (n = 55). The others with (n = 150) or without (n = 113) HPV suggestive lesions were followed-up only at 6-month intervals. Survival analysis was used to calculate the cure rates in different subgroups of the males, categorized according to the potential prognostic factors (i.e., age, treatment, lesion morphology, HPV type, female findings, and sexual habits). The calculated median cure time of the HPV-positive men was 15.2 months (95% confidence interval 12.2-21.3 months) and it did not differ significantly in the male groups treated or only followed-up (P = 0.56). In univariate survival analysis, only the ISH-positivity (P = 0.002) and the anamnestic use of condom (P = 0.05) were significant prognostic factors. The condom use also had a protective effect (P = 0.04) against the appearance of new HPV-suggestive lesions in initially healthy males. Although the treatment did not significantly affect the overall cure rate, the number of lesions decreased, however, after therapy (i.e., fewer widespread infections), and the appearance of new HPV lesions seemed to be less frequent in the treated than in nontreated males. The low success rate of therapy and the obviously benign clinical course of all subclinical HPV lesions of the male genitalia justify the follow-up of all lesions with HPV-suspicious morphology only. On the other hand, treatment seems to exert a favorable effect on clinical HPV infections, new exophytic warts and penile intraepithelial lesions (PIN) lesions being rare in adequately treated males.