Drug-resistant cell lines are useful for the study of the molecular basis of chemo-resistance. Due to changes in the adenosine 5´triphosphate binding cassette (ABC) transporters expression, these cells express dramatical increases in drug efflux through their surface membrane. We have selected a Leishmania strain [NR(Gr)] resistant to glibenclamide (GLIB), a drug which interacts with ABC transporters and analyzed whether the interaction of the parasite with its host cell changes for the resistant parasite. The data show that NR(Gr) incorporation is significantly increased in GLIB treated macrophages and that the intracellular parasite sensitivity against GLIB is regained. This reversion in drug sensitivity may be the result of an instability of the resistance during the infection and propagation of the intracellular stage of the parasite and could be related to an alteration in the expression of surface molecules in the parasite which may challenge its intracellular survival. These results emphasize the fact that understanding of the modulation of chemo-resistance could be relevant for the comprehension of the transmission of drug-resistant strains during the life cycle of Leishmania.Consejo de Desarrollo Cientifico y Humanistico de la UCV, Conicit-Venezuela,