INTRODUCTION: Cutaneous leishmaniasis is a common parasitic disease in Iran, especially in Isfahan. First line treatment for this disease is antimonial compounds; however, owing to the intermittent failure of this treatment and its significant side-effects alternative therapeutic measures have been advocated. OBJECTIVE: Evaluating the efficacy of pentoxifylline plus glucantime in the treatment of cutaneous leishmaniasis. METHODS: This double-blind, randomized, controlled clinical trial with simple sampling was performed on 64 patients with cutaneous leishmaniasis referred to the Skin Diseases & Leishmaniasis Research Center from an endemic foci of L. major in Isfahan. The patients randomly were divided into two groups. One group was treated with systemic Glucantime (20 mg pentavalent antimony/kg/day) combined with pentoxifylline (400 mg three times daily) and the other group were treated with Glucantime (20 mg pentavalent antimony/kg/day) plus placebo (three tablets daily) for 20 days. Follow up lasted 3 months. Response to treatment was grouped as complete improvement (lesions had been flattened, no induration, and epidermal creases had appeared), partial improvement (reduction in lesion size, but without the appearance of epidermal creases) and poor response (no reduction in lesion size). RESULTS: Of 64 participants, 32 patients in the trial group and 31 patients in the control group were followed for 3 months. One patient in group B discontinued withdrew. After this time, complete improvement, partial improvement and poor response to treatment were 81.3%, 12.5% and 6.2% in the trial group and 51.6%, 29% and 19.4% in the control group, respectively. We also observed no adverse effect resulting from pentoxifylline. DISCUSSION: The result obtained by two therapeutic methods indicates that combined therapy with Glucantime and pentoxifylline is more effective than Glucantime alone (P < 0.05).