There is a wide variety of topical or surgical treatment options for molluscum contagiosum (MC). However, treatment in young or anxious children is difficult, time-consuming and often painful. We studied the topical efficacy and tolerance of imiquimod, a topical immune-response modifier, which stimulates the production of interferon-alpha and other cytokines in children with MC. In an open-label, follow-up trial, imiquimod 5% cream was applied three times a week for 16 weeks to 15 children aged 4-11 years with multiple MC. Nine of 13 children (69%) who completed treatment responded. Two patients (15%) showed a complete remission, and seven (54%) had a partial response, with a remarkable reduction of the MC lesions. Four children (31%) showed stable or progressive disease. In three children (23%) with partial remission, the number of mollusca were considerably reduced, thus avoiding surgical treatment. In general, the treatment was well-tolerated, without systemic side-effects. Local side-effects included erythema (85%), itching (75%), burning sensations (23%) and pain (11%). Three children (23%) discontinued treatment because of local side-effects. The results of this study suggest that imiquimod 5% cream is a useful new treatment option for MC in children, especially in severe cases. The dosing schedule and length of treatment requires further evaluation.