In a retrospective study set in French Guiana, the efficacy and tolerance of the intramuscular treatment of cutaneous leishmaniasis (CL) with a single injection of pentamidine isethionate, at 7 mg/kg, were compared with those observed, earlier, using two such injections (given 48 h apart). Although 83.6% of the 281 patients given two injections each were cured, the single-injection protocol was generally as effective, curing 78.8% of 137 patients. The single-injection protocol was also associated with fewer adverse effects than the two-injection. In the treatment of "difficult" cases (those with satellite papules or relatively high numbers of amastigotes in their lesions), however, the two-injection protocol appeared significantly more effective than the single-injection. In French Guiana, therefore, patients with CL should be given one injection with pentamidine isethionate and only be given a second, 48 h later, if they have satellite papules and/or relatively high numbers of amastigotes in their lesions.