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Folate deficiency is implicated in cancer risk that may be modulated by a genetic variation in the methylenetetrahydrofolate reductase (MTHFR) gene in folate metabolism. We hypothesized that genetic variants inMTHFRare associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We genotyped 3MTHFRpolymorphisms (C677T, A1298C and G1793A) and estimated their haplotypes in a hospital-based case-control study of 537 SCCHN cases and 545 cancer-free controls. The controls were frequency-matched to the cases by age (± 5 years), sex, ethnicity and smoking status. We found that theMTHFR1298AC/CC genotypes were associated with an approximately 35% reduction in risk of SCCHN (adjusted odds ratio = 0.65; 95% CI = 0.51–0.82) compared to the AA genotype. TheMTHFR677CT and 1793GA/AA genotypes were associated with nonsignificant increased risk of SCCHN compared to the 677CC and 1793GG genotypes, respectively. We estimated that there were 8 haplotypes and 16 haplotype genotypes based on these 3 variants. When we used the haplotypes and assumed that the 677T, 1298A and 1793A alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0–1 variant, 1.85 (1.3–2.5) for any 2 risk alleles and 1.93 (1.4–2.7) for any 3 risk alleles. These results suggest that all 3MTHFRpolymorphisms may play a role in the susceptibility to SCCHN among non-Hispanic whites. Future studies should incorporate detailed data on alcohol consumption, dietary folate intake and related serologic measurements. © 2005 Wiley-Liss, Inc.