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We previously found that 2 mg of pentamidine isethionate/kg, administered every other day in seven injections, was 95% curative for Colombian cutaneous leishmaniasis. However, 17% of the patients had to prematurely terminate therapy due to drug toxicity and another 30% had mild-to-moderate toxic clinical reactions. In this report, we show that the same daily dose of drug, 2 mg/kg, but administered in only four every-other-day injections, resulted in an 84% cure rate in 38 patients. Twenty-one patients (55%) experienced side effects, three of which were moderate to severe. A higher daily dose of drug, 3 mg/kg, administered in four every-other-day injections, resulted in a 96% cure rate in 51 evaluable patients. Thirty-six of the treated patients (64%) experienced side effects, five of which were moderate to severe. Although hypotension and hypoglycemia were looked for in all patients, only one patient experienced hypoglycemia and it had normalized by follow-up. We propose that the regimen of 3 mg of pentamidine/kg every other day in four injections is optimal for Colombian cutaneous leishmaniasis and competitive with standard Glucantime therapy, in terms of cure rate, toxicity, length of time the patient has to be under medical supervision, and cost of drug plus medical attention. We suggest that such a short course of injectable agent be studied for the treatment of patients with cutaneous leishmaniasis from other endemic areas.