The p21 (Waf1/Cip1/CDKN1A) protein regulates the transition from the G1 to the S phase and has an important role in modulating cell-cycle control, apoptosis and cell growth. Two polymorphisms of the p21 gene at codon 31 (p21 C98A, dbSNP rs1801270) and at the 3' untranslated region (p21 T70C, dbSNP rs1059234) may have an effect on the protein function and may thus play a role in the development of cancer. We hypothesized that these two p21 polymorphisms are associated with the risk of squamous cell carcinoma of the head and neck (SCCHN). We tested this hypothesis in a hospital-based case-control study of 712 patients newly diagnosed with SCCHN and 1222 cancer-free controls who were frequency-matched by age, sex and ethnicity. All subjects were non-Hispanic whites. Our results showed that the variant alleles and genotypes were more common among cases than among controls (P < 0.001 and P = 0.013 for p21C70T, and P < 0.001 and P = 0.035 for p21C98A, respectively). Compared with the p21 70CC genotype, there was a significantly greater risk of SCCHN associated with the variant p21 70TC [odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.12-1.93] and combined p21 70TC/TT (OR = 1.49, 95% CI = 1.14-1.95) genotypes. Similarly, compared with the p21 98CC genotype, there was also a significantly greater SCCHN risk associated with the variant p21 98AC (OR = 1.32, 95% CI = 1.00-1.73) and combined p21 98AC/AA (OR = 1.37, 95% CI = 1.05-1.79) genotypes. When these two polymorphisms were evaluated together by the number of risk alleles, there was a significant increase in SCCHN risk that was dependent on the number of risk alleles (P(trend) = 0.001). Our results suggest that the presence of these two p21 polymorphisms may be a marker of genetic susceptibility to SCCHN.