In a case-control study, we tested the hypothesis that a previously described African American-specific polymorphism in an intron 3' to the coding region of the CYP1A1 gene was associated with the occurrence of lung cancer. The study population included 72 African Americans with newly diagnosed, untreated lung cancer who presented to collaborating clinicians at the University of Texas M.D. Anderson Cancer Center and from county, community and Veterans Administration hospitals in the Houston metropolitan area. Controls were 97 African Americans, frequency-matched on gender and age, recruited from community centers, churches, cancer screening programs and from among hospital employees. The prevalence of the variant CYP1A1 genotype did not differ between the cases and controls. The odds ratio for individuals with one or more copies of the variant allele was 0.64 [95% confidence interval (CI) 0.3-1.4]. Overall, 20.7% of the population had one or more variant alleles; the prevalence in cases was 16.7% and in controls it was 23.7%. Two individuals with the homozygous variant genotype were controls while one individual with lung cancer was found to have the homozygous variant genotype. The lack of an association between genotype and lung cancer persisted after subgroup analysis for lifetime cigarette smoking history and tumor histology was performed. The sample size of this study is sufficient to detect odds ratios of three or greater; associations of this magnitude are similar to those reported in studies of a different polymorphism in the same region of the CYP1A1 gene in Japanese. Thus, it is unlikely that this polymorphism is associated with sizable risks for tobacco-induced lung cancer in this population subgroup.