Background: A controlled study of the efficacy of topical paromomycin sulfate (PR) and methylbenzethonium chloride (MBCI) in cutaneous leishmaniasis (CL) has not yet been performed. Objective: The therapeutic effect of an ointment containing 15% PR and either 12% or 5% MBCI (15/12 or 15/5 P-ointment) on patients suffering from Old World CL was examined in a randomized, double-blind, cross-over study. Methods: Thirty-nine patients with Old World CL caused by Leishmania major were treated topically, twice daily, for 10 to 20 days with 15/12 or 15/5 P-ointment and 10 to 20 days with a placebo ointment to achieve a total of 30 days of treatment in all groups. Results: In the P-ointment-treated groups, 74.2% (29 of 39 patients) of the patients were cured versus 26.6% (4 of 15 patients) in the placebo-treated group. Little difference was found between the 15/12 and 15/5 P-ointment groups. Conclusion: In most of the patients treated with the active ingredients, total elimination of the parasites was achieved within the first 10 days of treatment.