In the current study, we not only showed that LMX1A hypermethylation was significantly associated with tumor size and poor 5-year overall survival rates and disease-free survival rates in early-stage CRC patients, but also demonstrated that the four-gene methylation panel, including NKX6.1, LMX1A, SOX1, and ZNF177, was a novel and independent prognostic tool for stage I and II, or stage II and III CRCs. Here, NKX6-1 is linked to neoplasm.