O6-methylguanine-DNA methyltransferase (O6-MT) probably plays an important role in the repair of chloroethylnitrosourea-induced DNA damage. O6-MT was studied as a possible drug resistance factor in two human lung cancer cell lines, one small cell lung cancer (U1690) and one non-small cell lung cancer (U1810), with different sensitivities to carmustine. The U1810 cell line was 3.4-fold more resistant to carmustine than U1690 cells, although the two cell lines were equally sensitive to mustine, melphalan and cisplatin. A 23-fold higher level of DNA interstrand crosslinks was observed following exposure of U1690 cells to carmustine compared with U1810 cells. The O6-MT activity of U1810 cells was 11 times higher than that of U1690 cells. The O6-MT activity in the U1810 cells showed a dose-dependent decrease after exposure to carmustine. These results show a correlation between increased O6-MT activity, decreased drug induced DNA interstrand crosslinking and cellular resistance to carmustine.