The utility of mitoxantrone (MTN) in the cytotoxic chemotherapy of human chronic myeloid leukemia (CML) is envisaged. In the present study we employed marginally toxic concentration of MTN and the antidepressant sintamil (SNT) as drug response modulator to evaluate the heterogeneous response to chemotherapy by CML cells and to potentiate the cytotoxicity of MTN. In vitro results from 26 different CML blood samples displayed variation in cytotoxicity of MTN (1 microgram/ml) alone alone and in the resulting synergistic inhibition of DNA biosynthesis with the combination of SNT (10 micrograms/ml). Of the 26 samples studied, 14 samples indicated synergistic, 2 additive, and 11 less than additive cytotoxic effects due to the combined treatment with MTN and SNT. The cytotoxicity induced by MTN alone and the combination with SNT was found to be irreversible. Data suggest the utility of MTN alone and in combination with SNT in the treatment of CML and warrant further studies for the evaluation in the clinics.