No study in China has focused on the relationships between germline and somatic hMLH1/hMSH2 gene mutations, hMLH1 promoter methylation, and the prognosis of colorectal cancer (CRC), especially in sporadic CRC. Therefore, we carried out this study with 433 primary sporadic CRC patients to investigate the associations between germline and somatic hMLH1/hMSH2 gene mutations, hMLH1 promoter methylation, and the overall survival (OS) of CRC; to evaluate the effect of interaction between gene mutation and methylation on the risk of CRC prognosis. As a result, the 3-, 5-, and 7-year survival of the sporadic CRC patients was 67, 57, and 50.0 %, respectively. There were no significant associations observed between germline and somatic hMLH1/hMSH2 gene mutations after adjusted (HR = 1.37, 95 % CI 0.70-2.67, p = 0.35; HR = 1.31, 95 % CI 0.69-2.47, p = 0.42, respectively). When the analyses were stratified based on tumor stage, tumor location, and chemotherapy, no significant survival advantage of hMLH1/hMSH2 gene mutation was illustrated. In addition, no significant association between germline and somatic hMLH1 promoter methylation and OS of CRC was observed (HR = 1.46, 95 % CI 0.57-3.74, p = 0.43; HR = 0.70, 95 % CI 0.32-1.53, p = 0.37, respectively). In conclusion, the research did not find the significant association between germline and somatic hMLH1/hMSH2 gene mutations, hMLH1 promoter methylation, and sporadic CRC prognosis.