Infantile hemangiomas (IHs) are the most common tumors of infancy. Imiquimod, an immune-response modifier, has been proven effective and safe in the treatment of superficial and mixed hemangiomas, but severe local reactions caused by imiquimod have been reported sporadically. To evaluate the safety of imiquimod 5% cream and the sequelae of severe local inflammatory reactions in the treatment of superficial IHs we performed a retrospective chart review of all children with superficial IHs who received topical imiquimod treatment in the Department of Plastic and Reconstructive Surgery of Shanghai 9th People's Hospital from March 2010 through February 2012 and selected those who had severe local reactions to topical imiquimod for further description. Nine of 224 (4.0%) children with superficial IHs who received imiquimod 5% cream treatment had severe local reactions. All four patients who had follow-up for longer than 1 year had permanent disfiguring depigmented scars after intensive inflammatory reactions. Seven of the severe reactions happened on protruding IHs and four involved the skin folds and joints, suggesting that imiquimod 5% cream should probably be avoided in IHs with either this morphology or these sites.