Background: Several treatment modalities have been used for cutaneous leishmaniasis (CL) with various results. In vitro and in vivo studies have shown inhibitory effects of zinc sulfate (ZnSO4) on Leishmania parasites. Objective: To compare the efficacy of intralesional injections of 2% ZnSO4 solution with meglumine antimonate (Glucantime) in the treatment of acute Old World CL. Patients and Methods: Seventy-two patients with CL with a duration of less than 8 weeks were recruited in a randomized, double-blind, clinical trial in Isfahan province – an area endemic for Leishmania major – after giving written informed consent. They were treated with 6 weekly intralesional injections of either 2% sterile ZnSO4 solution or Glucantime prepared in identical vials. The primary outcome measure was complete re-epithelialization of CL lesions. Results: Among 36 patients with 53 lesions treated with ZnSO4 and 36 patients with 53 lesions treated with Glucantime, 13 patients with 19 lesions and 22 patients with 31 lesions completed the trial, respectively. Inadequacy of treatment was the main reason for drop-out in 12 (33.3%) and 2 (5.5%) patients in ZnSO4 and Glucantime groups, respectively (P<0.05). Complete re-epithelialization was observed in 2 (10.5%) and 19 (61.3%) lesions 1 week after the end of treatment in the ZnSO4 and Glucantime groups, respectively (P<0.05). Conclusion: A six-week course of weekly intralesional injections of 2% ZnSO4 solution was less effective than Glucantime in the treatment of acute Old World CL.