A variety of resistance phenotypes to cytotoxic agents in bacteria, protozoa parasites and mammalian cells are mediated by evolutionarily conserved proteins of the mdr family. The finding that chloroquine resistance in the malarial parasite, Plasmodium falciparum, that is mediated by an mdr-1 gene product can be circumvented by tricyclic antidepressant drugs has stimulated the present study to assess whether this class of agents might also modulate the multidrug resistance (MDR) phenotype(s) in mammalian tumor cells. The possible chemosensitizing effects of nine antidepressant drugs have been tested against the UV-2237M murine fibrosarcoma line and its MDR variant. At nontoxic concentrations all nine antidepressants markedly enhanced the cytotoxicity of ADR against the parental cells but were much less effective against the MDR cells. The most active antidepressant, trazodone, also enhanced the cytotoxicities of vinblastine and vincristine, but not those of actinomycin D, mitomycin C, or 5-fluorouracil. The parental cells treated with trazodone exhibited an increased accumulation of intracellular ADR, but lacked detectable alterations in the expression and drug-binding activity of plasma membrane P-glycoprotein, and trazodone did not affect the activities of isolated protein kinase C and calmodulin. These data suggest that the antidepressant drug trazodone may be useful in the reversal of the intrinsic drug resistance of tumor cells that express low levels of P-glycoprotein.