Epidermolytic acanthoma is an uncommon benign tumor with a predilection for the anogenital region, that is characterized histologically by epidermolytic hyperkeratosis. Most reported cases are asymptomatic while some are pruritic. Treatment of this condition is challenging and not well studied. We report a 55-year-old man with pruritic anogenital epidermolytic acanthomas that persisted despite various topical and ablative therapies, and whose pruritus was not relieved with emollients and antihistamines. He was given 0.1% tacrolimus ointment twice daily and experienced a marked improvement in his pruritus within 2 weeks. At 1 month, there was marked improvement in itch score from 8 to 3.5 (maximum of 10), itch frequency from 20 times a day to once every 4 days, sleep score from 5 to 1 (maximum of 5), and Dermatology Life Quality Index score from 15 to 5 (maximum of 30). Apart from a transient burning sensation, no other adverse effects were noted. To our knowledge, this is the first report of the effective use of a topical calcineurin inhibitor in relieving the intractable itch associated with epidermolytic acanthoma.