To assess whether differences in genetic susceptibility to oxidative stress modify asbestos-related lung cancer risk (caused by lung inflammation, free radical production), we examined possible interactions between manganese superoxide dismutase (MnSOD) genotypes and asbestos in a hospital-based case-control study of 811 white lung cancer cases and 957 friend/spouse controls. Cumulative lifetime asbestos exposure score (AES) was calculated from self-reported duration and intensity of occupational and nonoccupational exposures. A total of 13.5% of cases and 10% of controls had "high" AES (determined by a priori cut point). The homozygous variant MnSOD genotype was associated with increased lung cancer risk among individuals with zero or "low" AES (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.52-3.01) and no association (OR = 1.00; 95% CI = 0.36-2.73) among the "high" AES group. We observed no statistically significant interaction between MnSOD genotype and asbestos exposure for lung cancer risk.