Fas-associated phosphatase-1 is encoded by the protein tyrosine phosphatase, non-receptor type 13 (PTPN13) gene and attributes to the resistance to Fas-mediated apoptosis in several tumors, including squamous cell carcinoma of the head and neck (SCCHN). However, no epidemiological studies have investigated the roles of PTPN13 polymorphisms in SCCHN risk. In this hospital-based case-control study of 1069 SCCHN patients and 1102 non-Hispanic white cancer-free controls, we evaluated the associations between three single-nucleotide polymorphisms c.4068 T>G F1356L (rs10033029), c.4566 A>G I1522M (rs2230600) and c.6241 T>G Y2081D (rs989902) located in the coding region of PTPN13 and SCCHN risk. We found that a significantly increased SCCHN risk was associated with the c.4566 I1522M GG genotype [odds ratio (OR), 1.89; 95% confidence interval (CI), 1.27-2.79] and c.6241 Y2081D GT genotype (OR, 1.26; 95% CI, 1.03-1.53) compared with the c.4566 I1522M AA and c.6241 Y2081D TT genotypes, respectively. Further stratified analyses showed that risk associated with the c.4566 I1522M GG genotype was more profound in the subgroups of young (< or = 57 years), males, never smokers, current drinkers and patients with pharyngeal cancer; that risk associated with c.6241 Y2081D GT genotype persisted in subgroups of old (>57 years), males, current drinkers and patients with pharyngeal and laryngeal cancers and that risk associated with c.6241 Y2081D GG genotype was borderline in patients with laryngeal cancer. In conclusion, polymorphisms in the PTPN13 coding region may be biomarkers for susceptibility to SCCHN in USA populations.