Two members of the mu class of glutathioneS-transferase (GST) genes,GSTM1andGSTM3, have polymorphic alleles which have been associated with altered levels of GST μ protein expression and may be linked to increased risk for several tobacco-related cancers. Oral cancer is a tobacco-related disease that affects African-American men at a significantly higher incidence than Caucasian men. To examine the potential role of GSTM polymorphisms in risk for oral cancer in African-Americans and Caucasians, the prevalences of theGSTM1null andGSTM3intron 6 polymorphisms were examined in 63 African-American and 101 Caucasian patients with histologically confirmed primary oral cancer, as well as in 133 African-American and 213 Caucasian matched control subjects. In African-Americans, the odds ratio for oral cancer associated with theGSTM1(0/0) genotype was 3.1 [95% confidence interval (CI) = 1.1–8.5], with the association between theGSTM1(0/0) genotype and oral cancer risk strongest in heavy smokers [i.e. > 24 pack-years; odds ratio (OR) = 5.4, 95% CI = 1.2–24]. Using the potentially most protectiveGSTM1[+]/GSTM3(B/B) genotype as the reference group, increased risk for oral cancer was observed in African-Americans with theGSTM1[+]/GSTM3[(A/A) + (A/B)] (OR = 2.2, 95% CI = 0.82–6.0),GSTM1(0/0)/GSTM3(B/B) (OR = 4.3, 95% CI = 1.1–16), andGSTM1(0/0)/GSTM3[(A/A) + (A/B)] (OR = 6.6, 95% CI = 1.2–38) genotypes (P< 0.01, trend test). No significant associations were observed betweenGSTMgenotype and oral cancer risk in Caucasians. These results suggest that theGSTM1null andGSTM3intron 6 polymorphisms play an important role in risk for oral cancer among African-Americans and implicates the mu class of GSTs as important tobacco carcinogen detoxifying enzymes in this population.