Tissue Factor Pathway Inhibitor 2 (TFPI2) is a serine protease inhibitor; it plays an important role in the degradation and remodeling of Extracellular Matrix (ECM). The degradation and reshaping of ECM is the basic steps of tumour growth and metastasis, angiogenesis, cell migration, and normal physiological processes. Therefore, TFPI2 plays a key in cancer, while it often silence by its promoter methylation. This study aimed to conduct a meta-analysis to access the relationship between TFPI2 promoter hyper-methylation and Colorectal Cancer (CRC). A detailed search of the literature was made using PubMed, Cochrane Library, Excerpta Medica Database (Embase), China National Knowledge Infrastructure (CNKI) and Web of Science for related research publications written in English and Chinese. The methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analyses of the pooled data were performed. Odds Ratios (ORs) were calculated summarized. A final analysis of 1,125 CRC patients from 13 eligible studies was performed. The pooled OR from 13 studies was OR=37.31 (Confidence Interval (CI)=22.06-63.12, p<0.00001). Aberrant TFPI2 hyper-methylation was significantly higher CRC than in normal control. This present study observed that TFPI2 hyper-methylation was significantly higher in CRC than in normal controls, which suggest that TFPI2 hyper-methylation is associated with an increased risk of CRC.