The aim of this paper was to evaluate the role of bcl-2 in the susceptibility of the MCF7 ADR human breast carcinoma line overexpressing the P-170 glycoprotein (P-170) to various drugs. The sensitivity to four multidrug resistance (MDR)-related drugs (doxorubicin (ADR), vincristine (VCR), vinblastine (VBL), actinomycin D (ACTD)) and three MDR-non-related drugs (cisplatin (DDP), bischloroethylnitrosourea (BCNU), 5-fluorouracil (5-FU)) was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay in three bcl-2-overexpressing clones obtained from the MCF7 ADR line. We found that the bcl-2-overexpressing clones show increased resistance to DDP and BCNU, while no difference to 5-FU were observed between the control cells and bcl-2 transfectants. Surprisingly, bcl-2-overexpressing clones displayed an increased sensitivity compared with the control cells to the MDR-related drugs ADR, VCR, VBL and ACTD. Focusing on DDP and ADR, we found that the increased resistance of the bcl-2 transfectants to DDP was correlated to their ability to prevent apoptosis, while the enhanced sensitivity to ADR was associated with an increased ADR accumulation and a decreased ADR efflux. Moreover, while bcl-2 overexpression does not induce changes in P-170 glycoprotein expression, it did induce a reduction of the adenosine triphosphate (ATP) levels and basal protein kinase C (PKC) activity, both of which have a crucial role in the regulation of the MDR phenotype. In conclusion, the effect of bcl-2 on antineoplastic sensitivity observed in this study underscores the idea that bcl-2 may have distinct biological effects depending on the anticancer drug used.