Although topical steroids are considered first-line treatment for cutaneous Langerhans cell histiocytosis (LCH), the appropriate therapy for refractory cases remains controversial. We report a 16-month-old girl with isolated cutaneous LCH refractory to treatment with topical corticosteroids and topical tacrolimus. Treatment was initiated with 5% topical imiquimod cream and the rash completely resolved after 5 months of therapy. There was no disease recurrence after more than 2 years of follow-up. We present this case to highlight imiquimod as a novel therapeutic agent for the management of isolated cutaneous LCH in children.