Polymorphisms in GSTM1, GSTT1 and GSTP1 genes in humans are associated with the reduction of enzymatic activity toward several substrates, including those in tobacco smoke. To investigate the potential role these polymorphisms have, as modulators of early-onset lung cancer risk, a population-based case-control study involving early-onset lung cancer cases was performed. Biological samples were available for 350 individuals diagnosed <50 years of age identified from the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program and 410 cases of age, race and sex-matched controls ascertained through random digit dialing. African Americans carrying at least one G allele at the GSTP1 locus were 2.9-fold more likely to have lung cancer compared with African Americans without a G allele after adjustment for age, sex, pack years of smoking and history of lung cancer in a first-degree relative (95% CI 1.29-6.20). African Americans with either one or two risk genotypes at the GSTM1 and GSTP1 loci were at increased risk of having lung cancer compared with those having fully functional GSTM1 and GSTP1 genes (OR = 2.8, 95% CI 1.1-7.2 and OR = 4.0, 95% CI 1.3-12.2, respectively). No significant single gene associations between GSTM1, GSTT1 or GSTP1 and early-onset lung cancer were identified in Caucasians, after adjusting for age, sex, pack years and family history of lung cancer. However, our results suggest that specific combinations of glutathione S-transferase polymorphisms increase the risk of early-onset of lung cancer. Joint analysis of these genotypes may identify individuals who are at a higher risk of developing early-onset lung cancer with a greater certainty than single gene studies.