Maintaining a high calcium concentration in the endoplasmic reticulum through the action of sarco/endoplasmic reticulum calcium-ATPases (SERCAs) is crucial in many cell functions involved in intracellular signal transduction, control of proliferation, programmed cell death, or the synthesis of mature proteins. Recent studies have found that many SERCAs have altered expression patterns in various malignancies. The purpose of the current study was to quantify the expression of SERCA2 in colorectal cancer (CRC) tissues and the corresponding noncancerous tissues, and to statistically analyze whether the SERCA2 expression levels correlate with the clinico-pathologic features and prognosis of CRC patients. Paired colorectal tissue samples from cancerous and the corresponding noncancerous tissues were obtained from 50 patients who underwent surgical resection. Semiquantitative measurements of SERCA2 messenger RNA (mRNA) expression were done using the multiplex reverse transcriptase-polymerase chain reaction. CRC tissues were analyzed through immunohistochemistry for the SERCA2 protein. SERCA2 mRNA overexpression in cancerous tissues compared with normal counterparts was observed in 45 of 50 (90%) patients. The mean expression level of SERCA2 mRNA in cancerous tissues was significantly higher than that in noncancerous tissues (P = 0.01). Increased SERCA2 protein expression was significantly correlated with serosal invasion (P = 0.012), lymph node metastasis (P = 0.009), and advanced tumor stage (P = 0.004). Furthermore, patients with high SERCA2 expression had a significantly poorer overall survival rate than patients with low SERCA2 (P = 0.032). Multivariate analyses indicated that tumor stage (P = 0.015) and SERCA2 expression were independently correlated with overall survival (P = 0.018). The result of this study indicated that SERCA2 may be a molecular determinant in the development and progression of CRC. The molecular mechanisms underlying the SERCA-dependent calcium accumulation and CRC tumorigenesis are worthy of further investigations.