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Atopic dermatitis is a common inflammatory condition of the skin. Moderate to severe cases not responding to topical treatments and lifestyle changes may need second-line therapy. Methotrexate has been suggested as an effective treatment in such cases.This study was done to determine the efficacy, adverse effects, and safety profile of methotrexate therapy in patients with atopic dermatitis.All adult patients with moderate to severe atopic dermatitis seen in the dermatology clinic at this tertiary hospital from January 2015 to December 2015 who were treated with methotrexate were reviewed in a retrospective chart review.Forty-one patients (19 female, 22 male, mean age 45 years, range 19-90 years) were enrolled. Of these, 29% were naive to any systemic treatments in the past, including systemic corticosteroids. Methotrexate treatment resulted in excellent improvement (>75%) in 93% of patients, good (50%-75% improvement) in 5%, and partial (25%-50% improvement) in 2%. Median duration of therapy was 26 months, and 80% of patients were still on treatment at last review. Transient nonsignificant elevation of transaminases was the most common adverse effect noted in 20%, followed by nausea in 12% and fatigue in 7%. A fibroscan was done in 10 patients at cumulative doses ranging from 2 to 11 g methotrexate. No liver fibrosis was seen in these patients.Methotrexate is an effective treatment for moderate to severe atopic dermatitis with an acceptable safety profile. A low dose can be used to control the disease for prolonged periods without significant risk.