Background: Cutaneous leishmaniasis is an endemic disease in developing countries. The first-line drugs for its treatment are the pentavalent antimony compounds such as meglumine antimoniate (MA). High cost, side effects, multiple injections and incomplete efficacy are limitations of this therapy. Zinc sulfate (ZS) has been reported to be effective in the treatment of cutaneous leishmaniasis. Objective: To compare the efficacy of intralesional injections of ZS 2% with those of MA in the treatment of cutaneous leishmaniasis. Methods: This was a prospective, double-blind, case-control clinical study. 104 patients with typical lesions of acute cutaneous leishmaniasis (ACL) were included. The duration of treatment was 6 weeks. Improvement was evaluated by clinical examination and direct smear. Results: The study was completed in only 66 patients: 35 patients received MA and 31 received ZS. The cure rates were 60% for MA and 83.8% for ZS. After the second and fourth weeks, the efficacy of treatment with ZS was higher than that with MA (p < 0.01), but after 6 weeks no significant differences were observed between the two groups (p > 0.05). Conclusion: On the basis of this trial and despite the high number of drop-outs, we consider that the intralesional injection of ZS 2% is an alternative treatment in ACL.