Abstract: Imiquimod has been reported to be efficacious in the topical treatment of uncomplicated infantile hemangiomas (IH). However, due to the natural tendency of IH to involute spontaneously, prior uncontrolled efficacy and safety studies have been called into question. We conducted a prospective self-controlled phase II study of imiquimod initially applied to uncomplicated, proliferative superficial or mixed IHs treating half of each IH once every other night for 16 weeks, leaving the other half untreated. After 16 weeks, an independent dermatologist evaluated the color, area, and volume of each half of the hemangioma. Of the 44 patients treated, the total effective rate was 80% (n = 35), with an overall resolution rated as excellent or good rate in 39% of lesions (n = 17/44). The relapse rate was 2% (n = 1). Side effects were noted in 61% (n = 27) including erythema or/and edema (n = 16%, 7), local itching (n = 7%, 3), peeling (n = 7%, 3), erosion (n = 5%, 2), crusting (n = 55%, 24), ulceration (n = 9%, 4), and scarring (n = 5%, 2). Some patients had two or more side effects. Most were judged to be mild to moderate and did not result in treatment being interrupted. Crusting or ulceration was noted to cause post-treatment skin reactions, such as texture change, whereas cases without crusting involuted to almost normal skin. No local infection or systemic reaction was observed. The difference in effective rate and side effect incidence between superficial and mixed IH was not statistically significant. Imiquimod 5% cream can be an effective and safe treatment option for superficial mixed IH in which the superficial component predominates. The recurrence rate is low, but local reactions including crusting can develop and result in post-treatment skin changes.