Background. Cutaneous leishmaniasis is a serious public health problem in the developing world. The main therapeutic agent - pentavalent antimony, developed >50 years ago - is expensive, often accompanied by severe adverse effects, and complicated by the emergence of drug resistance. Better therapies are urgently needed. In the present pilot study, we compared the use of imiquimod, an immunomodulatory molecule, to the use of meglumine antimoniate alone and in combination for the initial treatment of cutaneous leishmaniasis. Materials and methods. Patients with newly diagnosed cutaneous leishmaniasis were enrolled from a single referral center in Lima, Peru, from August 2005 through October 2005. Patients were randomly assigned to 1 of 3 treatment groups and received either imiquimod 7.5% cream administered topically every other day for 20 days, intravenous meglumine antimoniate administered at a dosage of 20 mg/kg per day every day for 20 days, or combination therapy with both intravenous meglumine antimoniate and imiquimod 7.5% cream. Patients were evaluated weekly and at 1 and 3 months after treatment. Patients who had healed lesions at 3 months were considered to be clinically cured. Results. Although several patients showed initial resolution of symptoms with imiquimod treatment alone, all of these patients experienced relapse after treatment discontinuation. Four (57%) of 7 patients treated with meglumine antimoniate alone and 7 (100%) of 7 patients treated with combination therapy were cured. Combination therapy was not only more effective than the other 2 treatments (P<.05) but also led to faster healing and better cosmetic results. Conclusion. Combination therapy with imiquimod and meglumine antimoniate is a promising regimen for the initial treatment of cutaneous leishmaniasis that warrants additional larger studies. © 2007 by the Infectious Diseases Society of America. All rights reserved.