Background: The incidence of overt genital warts, a common sexually transmitted disease of high prevalence, has been on the rise for the last few years. The infection is caused by several types of human papillomaviruses (HPVs), some of which have been accepted as a factor in the pathogenesis of genital squamous-cell carcinomas. Objective: The aim of this double-blind, placebo-controlled study was to compare and evidence differences in clinical efficacy and tolerance between human leukocyte interferon-α (2 × 106 IU/g) and podophyllotoxin (0.5%), incorporated in a hydrophilic cream base to cure genital warts in Asian males. Methods: Sixty patients, circumcised, who ranged in age from 18 to 40 years (mean 25.0), diagnosed with the evidence of penoscopy and HPV DNA (Southern dot blot) as harboring396 lesions (mean 6.6), were randomized to three parallel groups. Each subject was allocated a precoded tube (40 g) containing one of two trial preparations or matching placebo for 3 days’ (consecutive) usage, thrice daily. The study lasted 16 weeks with 4 weeks of active treatment. The patients were examined on a weekly basis, and a clinically and HPV-DNA-confirmed total regression of lesions was recorded as cured. Patients cured during the treatment were spared further therapy and were requested to visit us as scheduled for poststudy follow-up. Results: Findings indicated that patients treated with leukocyte interferon-α cream had shown comparatively better results than the podophyllotoxin-treated group (90 vs. 55%, p < 0.0285) or the placebo group (15%). Mild and transient localized erythema (8.3%), burning sensation (6.6%) and transitory increase in body temperature ( > 38 °C; 6.6%) were the most frequent adverse symptoms with no dropout. The study was followed up for 1 year, and out of 32/60 (53.3%) cured patients 3 had a relapse after 10 months. Conclusion: Leukocyte interferon-α (2 × 106 IU/g) has shown comparatively better results than 0.5% podophyllotoxin and placebo in a hydrophilic cream base, thus leukocyte interferon-α in cream may provide an alternative and effective regimen to treat genital warts in males.