OBJECTIVE: Programmed death-ligand 1 (PD-L1) expression in colorectal cancer (CRC) was implicated in predicting anti-PD-1/PD-L1 therapy efficacy. However, therapeutic response has also been found in patients without PD-L1 expression in the primary tumor. In the present study, we aimed to clarify the prevalence of PD-L1 in primary and metastatic CRC. METHODS: The expression of PD-L1 was determined by immunohistochemistry in matched primary and metastatic CRC. RESULTS: PD-L1 expression was significantly more prevalent in metastatic CRCs than in primary tumors, and the expression of PD-L1 in primary CRC may not represent the tumors that spread to distant organs. Positive expression of PD-L1 was found in 81.8% of metastatic CRC, being significantly more prevalent than in primary CRC (40.9%; P = 0.012, Fisher's exact test). While comparing the primary and metastatic lesions of the same patients, we found that PD-L1 expression frequently increased during the metastatic process. However, PD-L1 expression was rarely decreased in metastatic lesions. Intratumoral heterogeneity expression of PD-L1 was found in both metastatic CRC (22.2%) and primary CRCs (33.3%). PD-L1 was prevalently expressed in metastatic CRC, and increased PD-L1 expression was frequently found in metastatic CRC as compared to primary tumors. CONCLUSION: PD-L1 expression in metastatic CRC should be considered as an independent factor while evaluating the suitability of patients for immunotherapy.