In the south of France, leishmaniasis due to Leishmania infantum occurs in the following five foci of endemicity (from west to east): Pyrénées-Orientales, Cévennes, Provence, Côte d'Azur, and Corsica. Between 1981 and 2002, 712 Leishmania strains obtained from humans, dogs, cats, and sand flies were studied by isoenzyme analysis. In total, seven zymodemes were identified: MON-1, MON-11, MON-24, MON-29, MON-33, MON-34, and MON-108. The Pyrénées-Orientales focus is characterized by a predominance of human cutaneous leishmaniasis and a high enzymatic polymorphism (five zymodemes). In the other foci, where human visceral leishmaniasis is predominant, only two zymodemes are present. L. infantum MON-1 is the parasite most frequently found, in patients both with and without concomitant human immunodeficiency virus infection. MON-1 is the only zymodeme present in dogs, which act as the reservoir host in all of the foci. In Cévennes, where the complete life cycle of zymodeme MON-1 has been identified, Phlebotomus perniciosus and Phlebotomus ariasi are vectors. The enzymatic polymorphism is compared to that of neighboring countries (Spain and Italy). In Pyrénées-Orientales, small variant zymodemes with electromorphs of heterozygote-like and homozygotic patterns can be explained by different genetic hypotheses.