Recent studies have suggested that a perturbation of intracellular Ca(2+) homeostasis or signaling could contribute to cancer development. The purpose of this study was to evaluate whether germline variants of the ATP2A2 and ATP2A3 genes might act as susceptibility alleles in head and neck squamous cell carcinoma. In both genes, we identified eight different alterations in 11 patients with head and neck squamous cell carcinoma (11/79; P = 0.0002, odds ratio = 0.054, 95% confidence interval = 0.0069-0.4236). We also detected low expression level of both genes in connection with some of alterations, but could not correlate low expression level with methylation in the promoter region of either gene. The results suggest that Ca(2+) pumps of sarcoplasmic-endoplasmic reticulum are involved in an increased susceptibility to develop head and neck squamous cell carcinoma in humans.