Abstract: Our aim was to study the effects and safety of cantharidin in the treatment of molluscum contagiosum (MC), we conducted a prospective, double-blinded, placebo-controlled, randomized clinical trial to evaluate the safety and efficacy of topical cantharidin for treatment of pediatric MC in an academic ambulatory care center. Twenty-nine children aged 5–10 with a diagnosis of MC were enrolled to receive treatment with cantharidin or placebo. The main outcome measure was complete clearance of all molluscum lesions. In contrast to previous retrospective observational studies, the performance of cantharidin treatment over 2 months was not substantially better than the performance of placebo. The scope of follow-up was limited to five visits over 2 months of treatment. A longer follow-up period might have captured a greater effect of cantharidin. Over a 2 month period, the magnitude of the cantharidin treatment effects in the target population are, at best, not large. This study provided objective unbiased estimates of the magnitude of cantharidin treatment effects and provided important prospective safety data. Our subjects experienced minimal side effects when treated with cantharidin.