Our objective was to characterize biologically in an animal model two isolates of Leishmania parasites unexpectedly encountered in the circulating blood of two patients with chronic cutaneous leishmaniasis. Both isolates were classified by cellulose acetate electrophoresis as belonging to the L. donovani senso lato complex. We elected to use BALB/c mice, an inbred strain that has been proven to be very sensitive to the dermotropic parasite L. major. This study demonstrated that for the same number of parasites, the course of infection with the L. donovani strain was different from that developed in similar animals that received the L. major strain. After a protracted incubation period, L. donovani produced scanty cutaneous lesions and mainly a systemic disease. This is in contrast to the rapidly spreading skin lesion that kills L. major-infected animals within a few months. It is concluded that BALB/c mice are an adequate animal model for the L. donovani strain, which had an unusual clinical presentation in humans. The prolonged incubation period, such as observed here, may lead to erroneous conclusions of host resistance if the experiment were terminated based on L. major activity in the same model. Finally, the unusual behavior in humans and mice of certain strains (such as the one encountered in these patients) must reflect peculiar intrinsic features of the parasite, which are best understood using animal models in the laboratory.