Inactivation of p16(INK4a) in the Rb pathway is among the most common somatic alterations observed in nonsmall cell lung cancers (NSCLCs). While epigenetic inactivation of the p16(INK4a) gene promoter has been shown to be associated with increased tobacco carcinogen exposure, little investigation of any similar association of homozygous deletion or mutation of p16(INK4a) and tobacco use has been completed. In 177 consecutive NSCLCs, we examined the determinants of p16(INK4a) homozygous deletion and mutation, including the pattern of tobacco smoking and asbestos exposure. We observed that p16(INK4a) homozygous deletion occurred at a higher frequency in never smokers as compared to former and current smokers (p = 0.01). This observation suggested that tumors from these patients might be more prone to DNA deletion events; consistent with this, epigenetic silencing of the DNA double-strand break repair genes FancF and BRCA1 was also associated with homozygous deletion of p16(INK4a)(p = 0.002 and p = 0.06, respectively). Finally, mutation of p16(INK4a) was rare and only occurred in patients who were smokers. Hence, the character of somatic alteration in the Rb pathway (deletion, mutation or methylation silencing) in NSCLC is associated with the pattern of tobacco exposure, suggesting that susceptibility to lung cancer is, at least in part, mediated by the biological mechanism that selects for the character of the induced somatic lesion.