With systematic bioinformatics screening and clinical verification, our study showed that a combination of serum CK20 and hyper-methylated CLIP4 was a novel and effective biomarker for CRC diagnosis with 91.67% sensitivity and 82.54% specificity in the training cohort; and 95% sensitivity and 81.7% specificity in the validation cohort. The gene discussed is CLIP4; the disease is colorectal carcinoma.