Vitamin D has potent anti-tumour properties. Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including human squamous cells of the head and neck. Several polymorphisms of the vitamin D receptor (VDR) gene have been described, including a FokI restriction fragment-length polymorphism (RFLP) in exon 2 and an adjacent TaqI RFLP in exon 9. We hypothesized that the VDR FokI and TaqI polymorphisms are associated with the risk of developing squamous cell carcinoma of the head and neck (SCCHN). We conducted a hospital-based, case-control study of 719 SCCHN cases and 821 cancer-free controls (all non-Hispanic Whites) to assess the association between VDR polymorphisms and SCCHN risk. The cases and controls were frequency-matched on age, sex and ethnicity. Polymorphisms at the TaqI and FokI restriction sites were determined from genomic DNA by polymerase chain reaction-RFLP methods. Both homozygous variant genotypes (ff and tt) were associated with a decreased risk of SCCHN [odds ratio (OR)=0.72, 95% confidence interval (CI)=0.53-0.98 and OR=0.64, 95% CI=0.47-0.87, respectively] compared to the common FF and TT genotypes. The VDR variant genotypes were associated with a decreasing risk of SCCHN in a variant allele dose-dependent manner, and the decreasing trend in OR was statistically significant, particularly for the combined genotypes (Ptrend<0.001). These data suggest that the VDR f and t alleles and their genotypes may protect against SCCHN. However, further studies are warranted to confirm these findings.