Imidazoles such as ketoconazole have proven antileishmanial activity, both in vitro and in vivo. New derivatives of ketoconazole have been synthesized in order to improve the therapeutic index and antileishmanial activity as assessed by mouse peritoneal macrophages infected with Leishmania mexicana amazonesis. Amino-acid derivatives of ketoconazole are at least 10 times more effective than ketoconazole in vitro, and the best effect is observed using the phenylalanyl-ketoconazole. Fatty acid derivatives, such as oleoyl-ketoconazole, also possess a greater therapeutic activity but to a lesser extent than amino-acid derivatives. Moreover, oleoyl-ketoconazole showed a remarkable property in terms of effective dose. Our results demonstrate the potential antileishmanial efficacy of some ketoconazole derivatives, and suggest that phenylalanyl-ketoconazole should be considered for experimental evaluation in animal models.