In this study, we first classified CRC samples into three methylator groups, SDC2/TFPI2 double-positive group (HH, high-methylation/high-methylation), SDC2/TFPI2 single positive group (HL, high-methylation/low-methylation), and SDC2/TFPI2 double negative group (LL, low-methylation/low-methylation) according to the promoter methylation status of SDC2 and TFPI2. The clinical-pathological parameters and molecular features were then evaluated by inner and outer cohorts, including TCGA, GEO, and our D311 CRC dataset. The gene discussed is TFPI2; the disease is colorectal carcinoma.