Background: Cutaneous leishmaniasis (CL) is a major world problem. Several types of treatment regimens have been suggested. Imiquimod demonstrated a leishmanicidal activity by increasing local cytokine production. The aim of this study was to determine the efficacy of topical 5% imiquimod with cryotherapy vs. intralesional meglumine antimoniate (MA) in treatment of anthroponotic (dry type) CL. Method: This is a prospective, randomized, open trial study (from Iran) from September 2008 to September 2010, including 50 patients (25 patients in the combined imiquimod and cryotherapy group and 25 patients in the intralesional MA group). Patients were randomly assigned to receive combined cryotherapy biweekly with imiquimod three times per week or intralesional MA weekly until complete cure or up to 12 weeks, whichever earlier. The primary end point was clinical cure, defined as complete re-epitelialization of 100%, complete flattening of induration compared with baseline at weeks 2, 6, 12 and follow up were done 1, 2 and 3 months after complete cure. Results: 50 participants divided into 25 patients in group A and 25 patients in group B completed the study. Complete cure was 65.5% (16/24 patients) in group A and 83.3% (19/23 patients) in group B. No complication was detected in patients treated with MA. Pain and eczematous reaction were detected by 4 patients and local infection in 1 patient treated with imiquimod. Conclusion: Although Meguimine antimoniate seems to be a more effective therapy for cutaneous leishmaniasis, this study revealed no significant difference in clinical response between combination of imiquimod and cryotherapy with intralesional MA in patients with cutaneous leishmaniasis in an endemic area of L. tropica.