BACKGROUND/AIM: We investigated the association of the levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) with prognosis in patients with stage IV colorectal cancer at diagnosis. PATIENTS AND METHODS: In this multicenter retrospective cohort study, patients with serum CEA and CA19-9 measured at diagnosis of stage IV colorectal cancer were included. The cutoff values were 5 ng/ml for CEA and 37 U/ml for CA19-9. Patients were categorized into four groups: those with normal levels for both CEA and CA19-9; those with only an elevated CEA level; those with only an elevated CA19-9 level; and those with elevated levels of both. RESULTS: A total of 825 patients were included. Among them, 132 (16.0%) had normal levels for both markers, 258 (31.3%) had an elevated CEA level only, 33 (4.0%) had an elevated CA19-9 level only, and 402 (48.7%) had elevated levels of both CEA and CA19-9. Compared with patients with normal levels for both CEA and CA19-9, the multivariate hazard ratio for overall survival was 1.24 (95% confidence interval=0.95-1.62, p=0.12) for those with elevated CEA only, 2.04 (95% confidence interval=1.31-3.17, p=0.002) for those with elevated CA19-9 only, and 1.82 (95% confidence interval=1.41-2.32, p<0.001) in those with elevation of both CEA and CA19-9. CONCLUSION: Elevation of CEA alone was not prognostic. Elevation of only CA19-9 at diagnosis was associated with a worse prognosis in patients with stage IV colorectal cancer. The combined measurement of CEA and CA19-9 can be helpful as a predictive tool for the prognosis of stage IV colorectal cancer.