A previously published case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found a significant relationship of serum levels of total NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides) to prospective lung cancer risk. The present paper examines this relationship in the context of single-nucleotide polymorphisms (SNPs) in genes important in the metabolism of tobacco smoke carcinogens. DNA was extracted from the subjects' lymphocytes and analyzed for SNPs in 11 locations on four genes related to tobacco carcinogen metabolism. Logistic regressions on case-control status were used to estimate main effects of SNPs and biomarkers and their interactions adjusting for potential confounders. Of the 11 SNPs, only one, in CYP1B1, significantly interacted with total NNAL affecting risk for lung cancer. At low NNAL levels, the variant appeared protective. However, for those with the minor variant, the risk for lung cancer increased with increasing NNAL five times as rapidly compared to those without it, so that at high NNAL levels, this SNP's protection disappears. Analyzing only adenocarcinomas, the effect of the variant was even stronger, with the risk of cancer increasing six times as fast. A common polymorphism of CYP1B1 may play a role in the risk of NNK, a powerful lung carcinogen, in the development of lung cancer in smokers.