SULT1A1 enzyme is a member of the sulfotransferase family that alters biological activities of numerous carcinogenic and mutagenic compounds through sulfation. A genetic polymorphism in the coding region of SULT1A1 gene has been associated with modulated enzyme activity. There is a G-->A nucleotide polymorphism in SULT1A1 gene that codes for an Arg-->His substitution, which results in decreased activity and thermal stability of the SULT1A1 enzyme. Utilizing a case-control study design, we hypothesized that the variant allele of the SULT1A1 gene may be associated with lung cancer risk. The PCR-RFLP assay was used to successfully genotype the SULT1A1*2 allele (variant A-allele) in 463 Caucasian lung cancer cases and 485 frequency matched Caucasian controls. There was an overall significant difference between cases and controls when adjusted by sex and smoking status (adjusted OR=1.41, 95% CI: 1.04-1.91). The adjusted OR was higher for females (OR=1.64, 95% CI: 1.06-2.56) than for males (OR=1.23, 95% CI: 0.80-1.88). Furthermore, the risk was significantly higher in current smokers (OR=1.74, 95% CI: 1.08-2.29) and heavy smokers (OR=1.45, 95% CI: 1.05-2.00). Our results support the hypothesis that a genetic polymorphism in the SULT1A1 gene may be associated with increased lung cancer risk.