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In the present retrospective study, we investigated the prognostic significance of caudal-type homeobox transcription factor 2 (CDX2) expression in metastatic colorectal cancer (CRC). We found that the median overall survival and progression-free survival for first-line chemotherapy were markedly decreased in patients with CDX2-negative metastatic CRC. These results support the lack of CDX2 expression as a potential prognostic biomarker for metastatic CRC.Although the lack of CDX2 expression has recently been proposed as a potential biomarker for a high risk of relapse in patients with stage II and III colon cancer after complete surgical resection, its prognostic role in metastatic colorectal cancer (CRC) remains unclear and warrants investigation.We identified 145 patients treated at our institution from 2006 to 2016, including 66 patients with CDX2-negative metastatic CRC and a comparison cohort of 79 patients with CDX2-positive metastatic CRC. Overall survival (OS) and progression-free survival (PFS) for first-line systemic therapy were estimated using the Kaplan-Meier method. The associations of CDX2 expression with survival were evaluated using Cox proportional hazards regression models.The prevalence of absent CDX2 expression in our cohort was 5.6%. Patients with CDX2-negative metastatic CRC were significantly more likely to be female, and to have right-sided primary tumors, poorly differentiated histologic features, and distant lymph node metastasis. The median OS for patients with CDX2-negative and -positive metastatic CRC was 8 and 39 months, respectively (hazard ratio [HR], 4.04; 95% confidence interval [CI], 2.49-6.54; P < .0001). After adjusting for covariates in a multivariate model, the association of a lack of CDX2 expression and OS remained statistically significant (HR, 4.52; 95% CI, 2.50-8.17; P < .0001). In addition, the median PFS (3 vs. 10 months; HR, 2.23; 95% CI, 1.52-3.27; P < .0001) for first-line chemotherapy was significantly decreased in patients with CDX2-negative metastatic CRC.The results of the present study show that a lack of CDX2 expression in metastatic CRC is an adverse prognostic feature and a potential negative predictor of the response to chemotherapy.