PURPOSE: Sulfotransferases (SULT) 1A1 detoxify and bio-activate a broad spectrum of substrates including xenobiotics. The SULT1A1 gene possesses a G-->A polymorphism that results in an Arg to His substitution at codon 213, with the His allele having a low activity. The purpose of this study was to evaluate whether SULT1A1 Arg213His polymorphisms are risk factors for head and neck squamous cell carcinoma (SCCHN). METHODS: A total of 124 consecutive primary SCCHN patients and 249 age- and sex-matched hospital controls were enrolled in this study. Genomic DNA was isolated from peripheral blood lymphocytes and genotyping was performed by PCR-RFLP. A comprehensive epidemiological interview was conducted on all participants to collect their lifestyle data. RESULTS: The His/His frequencies in cases and controls were 6.5% (8/123) and 3.6% (9/247), respectively (P=0.049). Multivariate logistic regression analysis showed a significant association of SCCHN and His/His genotype (OR=3.60; 95% CI=1.01-12.88). This association was stronger amongst older people, alcohol and low fruit consumers. The resulted SULT1A1 His/His genotype also associated with a higher risk of neck node positive status (OR=5.82; 95% CI=1.10-30.68). CONCLUSIONS: These preliminary findings show for the first time that the SULT1A1 His (213) allele is a possible risk factor for head and neck cancer development.