Background: Epidermal nevus syndrome is a multi-system disease with a wide spectrum of clinical presentation. Numerous specialists may be required to address its extra cutaneous manifestations.Main observations: We report a severe case of epidermal nevus syndrome involving the oral cavity, pharynx, and central nervous system in addition to disfiguring skin lesions.Conclusions: Dermatologists are in a unique position to first render the diagnosis of epidermal nevus syndrome for young patients and ensure appropriate follow-up. (J Dermatol Case Rep. 2011; 5(2):