Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Polyhexamethylene biguanide is a new agent, that has been demonstrated to have potent in vivo antiviral effects in animal and in human models. The present prospective, double-blind, randomized, placebo (vehicle-controlled) trial evaluated the efficacy and safety of daily patient-applied polyhexamethylene biguanide for up to 16-weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with polyhexamethylene biguanide cream versus and 3 of 95 (4%) placebo patients; the differences between the groups treated with placebo and polyhexamethylene biguanide were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the polyhexamethylene biguanide cream group, 17% cream group, and 0% (0 of 3) in the placebo group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common in the polyhexamethylene biguanide cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied polyhexamethylene biguanide cream is effective for the treatment of external genital warts and has a favorable safety profile.