Abstract Background Circulating tumor DNA (ctDNA) is a biomarker with potential to reflect comprehensive genomic information and overcome intratumor heterogeneity. In contrast, carcinoembryonic antigen (CEA) is a conventional tumor marker for predicting recurrence, survival, and chemotherapeutic efficacy in patients with metastatic colorectal cancer (mCRC). However, the relationship between them remains unclear. Here, the relationship between plasma ctDNA and CEA levels was evaluated to clarify the advantages and disadvantages of their clinical use. Methods A total of 110 patients with mCRC underwent chemotherapy were enrolled. Amplicon‐based plasma genomic profiling of 14 genes that are commonly mutated in CRC by next‐generation sequencing was compared to the CEA level and tumor diameter using Spearman’s correlation coefficient. Results The overall concordance rate between the ctDNA and CEA levels was 75.5% (83/110). The correlation coefficient between the ctDNA and CEA levels was lower in the group of patients without liver and lymph node metastases (r = 0.18, p = 0.44) than in the group of patients with liver metastasis (r = 0.48, p