BACKGROUND & OBJECTIVES: Pentavalent antimony compounds are the first line of drugs in the treatment of cutaneous leishmaniasis. However, because of their potential toxic effects, many investigations are performed to find an effective and safe treatment for cutaneous leishmaniasis patients. Our objective in this investigation was to compare the effect of oral omeprazole and low dose systemic meglumine antimoniate (MA) and standard dose of systemic MA in the treatment of cutaneous leishmaniasis. METHODS: This was a randomized double-blinded clinical trial. In 150 patients with cutaneous leishmaniasis who were randomly divided into three groups and were treated with: (i) MA 60 mg/kg/day/ IM and oral placebo for three weeks; (ii) MA 30 mg/kg/day/IM and oral omeprazole 40 mg/day for three weeks; and (iii) MA 30 mg/kg/day/IM and oral placebo for three weeks. All the patients were visited every two weeks from the beginning of the trial up to six weeks and then at 8 and 12 weeks. The effectiveness of the treatment was classified in three levels as complete response, partial response and no response. Data were analyzed by SPSS 10 using KI square, Mann-Whitney, Kaplan-Mayer and ANOVA tests. RESULTS: Rate of complete response for three months (12 weeks) after starting the treatments was 93% for the group treated with standard dose of glucantime and placebo, 89% for the group treated with omeprazole and low dose glucantime and 80% for the group treated with low dose glucantime and placebo and these differences were significant (p < 0.05). The highest response rate was for the group treated with standard dose of glucantime and placebo. INTERPRETATION & CONCLUSION: Although oral omeprazole and low dose of systemic MA showed less efficacy in comparison to standard dose of systemic MA in the treatment of cutaneous leishmaniasis, it still can be considered as a replacement therapy in high risk patients (such as patients with heart, kidney and/or liver disease) under close supervision of physician.