Background: Molluscum contagiosum is generally a self-limiting benign skin disease that affects mostly children and young adults. Objective: The purpose of this multicenter, double-blind, placebo-controlled study was to compare the clinical efficacy and tolerance of 0.3% and 0.5% podophyllotoxin in a hydrophilic cream base to cure molluscum contagiosum in Asian males. Methods: Preselected patients (n = 150), age range 10–26 years (mean: 15.4), harboring 1,125 lesions (mean: 7.5), with size ranging from 2 to 8 mm in diameter (mean spot size 3.2 mm) and biopsy-proven diagnosis of molluscum contagiosum, were randomly allocated to three parallel groups. Twenty-four (16%) patients had atopic dermatitis. Patients self-administered placebo, 0.3% or 0.5% podophyllotoxin cream, twice daily for 3 consecutive days, and if total elimination was not achieved with one trial (6 topical applications), the same treatment was extended to 3 more weeks (24 topical applications in 4 weeks). The duration of the study was 12 weeks with 6 months (on monthly basis) follow-up. By the end of the treatment 80 patients (52, 92 and 16% patients in the 0.3%, 0.5% and the placebo groups, respectively) were evaluated as completely cured. During the treatment 92 patients (61.3%) did not complain of any allergic or localized adverse symptoms. Tolerable moderate to mild frequent side effects were pruritus (20.6%) and erythema (18%), with no dropouts. No recurrence was seen after 9 months of follow-up. Response to the trial medications appeared to be directly proportional to the concentration of podophyllotoxin (p < 0.001). Self-medication was well accepted by all the patients. It was concluded that the 0.5% podophyllotoxin cream preparation was more efficacious than the 0.3% incorporation (p < 0.001) and can be considered a safe, home-based first line of therapy to cure molluscum contagiosum.