Background: Epidermal nevus is a common skin hamartoma. Its definite treatment is difficult and in most cases the disease has recurrence. Objective: Evaluation of topical tretinoin 0.05% and 5 Fluorouracil (5FU) 5% in the treatment of epidermal nevus. Patients and Methods: Fifteen patients with epidermal nevus referred to skin clinic in Razi Hospital in Tehran whose diagnoses were confirmed by pathology examination, were treated with topical tretinoin 0.05% and 5FU 5%. Five patients were excluded because of loss to follow up and 10 patients were regularly followed. Results: Four patients were male and 6 of them were female. Their age ranged from 12 to 40 years. After 10 weeks, their nevi were flattened considerably so the patients were satisfied. There was no complication that needed to stop the treatment completely. Maintenance treatment was recommended and no recurrence was seen until the end of follow up duration. Conclusion: Topical tretinoin 0.05% and 5FU 5% are easy and inexpensive treatments for epidermal nevi, with satisfactory results and long maintenance therapy will prevent recurrence.