Silencing of tumor suppressor genes by hypermethylation in gene promoter regions is a crucial mechanism in carcinogenesis. Gene methylation may be reversible and evaluated easily, thus providing a promising substrate for the development of biomarkers for the detection and prevention of cancer, including colorectal cancer (CRC). In the present study, the protein expression and methylation status of smooth muscle protein 22 alpha (SM22 alpha) was investigated in 78 cases of CRC and adjacent normal tissue. The aim of the study was to investigate the function of SM22 alpha in the pathogenesis of CRC and to identify a candidate biomarker for the early detection of CRC. The methylation status of promoter of SM22 alpha gene was detected using methylation-specific polymerase chain reaction. The protein expression of SM22 alpha was evaluated using western blot analysis. The results demonstrated a significant decrease of SM22 alpha protein expression in 50 (68.5%) cases of CRC compared with that in adjacent normal tissues (P < 0.001). The methylation status of SM22 alpha promoter in CRC was significantly increased compared with that in adjacent normal tissues (P < 0.001). Additionally, there was a negative correlation between the expression of SM22a protein and methylation levels of SM22 alpha gene in CRC (P < 0.001). Kaplan-Meier curves revealed that patients with CRC with an unmethylated promoter of SM22 alpha gene exhibited an increased survival time (34.8 +/- 0.6 vs. 30.9 +/- 1.3 months; P=0.025) compared with that in patients with a methylated promoter of SM22 alpha gene. The present study demonstrated that the protein expression of SM22 alpha is downregulated in CRC tissues by hypermethylation of its promoter, and that the methylation of SM22 alpha promoter may be used as a biomarker for early detection, prognosis and prediction of CRC.