A 35-year-old man with a 19-year history of slowly evolving diffuse cutaneous leishmaniasis was treated with oral miltefosine, 50 mg three times a day. The patient responded after four months of miltefosine treatment with clearance of all nodular lesions and plaques from the entire body surface and had negative slit-skin smears and cultures for Leishmania. However, two months after stopping miltefosine, skin lesions reappeared and parasites were observed in samples. The relapsed lesions did not respond to an additional two-month course of miltefosine. No laboratory or clinical adverse events to miltefosine were observed. Parasites from skin lesions were cultured and identified as Leishmania (Leishmania) mexicana by isoenzyme electrophoresis.