The relationship between O6-methylguanine-DNA methyltransferase (O6-MT) activity and the sensitivity of 4 kinds of human tumor cell lines to bis-chloroethylnitrosourea (BCNU) was evaluated. The results demonstrated that cellular resistance to BCNU was linearly correlated with O6-MT activity, suggesting that O6-MT plays an important role in repairing DNA damage induced by BCNU. Furthermore, the depletion of O6-MT activity by streptozotocin (STZ) pretreatment and its effect on the cell's sensitivity to BCNU were investigated. O6-MT activity could be efficiently reduced, and sensitivity to BCNU was subsequently increased significantly. There was also a linear correlation between depletion of O6-MT activity and enhancement of BCNU's cytotoxic effects. These results indicate that O6-MT might constitute the molecular basis of cellular resistance to BCNU, and a combination of STZ and BCNU may result in better therapeutic effects.