Sarcoendoplasmic reticulum calcium transport ATPases (SERCAs) accumulate Ca2+in the endoplasmic reticulum and are essential molecules in calcium-mediated signaling. Some reports indicate that down-regulation of these enzymes is closely associated with carcinogenesis. We thus hypothesized that the ATP2A2 gene, coding SERCA 2 protein, may be associated with oral carcinogenesis. Forty lower gingival squamous cell carcinomas (SCCs), 20 gingival premalignant lesions (leukoplakias), and adjacent normal tissue samples were examined. Immunohistochemical studies revealed strong expression of SERCA2 protein in all normal tissues and significantly down-regulated expression of SERCA2 protein in 45% of SCCs. Expression of SERCA2 in the premalignant lesions tended to decrease, but was higher than that in SCCs. Moreover, analyses according to clinical and pathological classifications indicated that the decreased SERCA2 protein expression in lower gingival SCCs correlated with the progression of carcinogenesis and the extent of malignancy. These results suggested that ATP2A2 gene expression might be altered in relation to the clinical profiles of lower gingival SCCs.