Efficacy of combination chemotherapy depends on the probability of a cell being resistant to at least two drugs simultaneously. In this study, we determined the frequencies of double drug resistance in the CHO AA8 cell line under combined exposure to vincristine plus adriamycin, vincristine plus etoposide, and adriamycin plus etoposide. These frequencies were compared to the expected frequencies which are the product of the independent frequencies observed for each drug alone. The results show a high frequency (up to 700-fold) of double resistance to adriamycin plus vincristine, a low increase (up to 30-fold) in frequency of resistance to vincristine plus etoposide, and an intermediate increase (200 to 300-fold) in frequency of cells resistant to adriamycin plus etoposide. The differences observed between combinations seem to be related, at least in part, to the mechanism(s) of resistance generally involved in the resistance to each drug: P-glycoprotein overexpression and/or DNA topoisomerase II alteration.