OBJECTIVE The aim of this study was to evaluate the clinicopathological significance and prognostic role of programmed death-1 ligand 2 (PD-L2) expression in colorectal cancer according to intratumoral components. METHODS We used immunohistochemical analysis to investigate the impact of PD-L2 expression on clinicopathological characteristics and survival in 264 human colorectal cancer tissues. We also evaluated the correlation between PD-L2 expression and PD-L1 expression. RESULTS PD-L2 was expressed in 17.4% of the tumors (T-PD-L2) and in 19.3% of the immune cells (I-PD-L2) of the 264 CRC tissues. I-PD-L2 expression was significantly correlated with favorable tumor behaviors, including lower pathologic tumor stage, less lymph node metastasis, less distant metastasis, and lower pathologic tumor node metastasis stage. There was no significant correlation between I-PD-L2 expression and T-PD-L2 expression (P = 0.091). However, I-PD-L2 expression was correlated with PD-L1 expression in the immune cells (P < 0.001). There was also a significant correlation between high Immunoscore and I-PD-L2, but not T-PD-L2 (P < 0.001 and P = 0.190, respectively). The prognosis was better for patients who expressed I-PD-L2 than for patients who did not. In patients who expressed I-PD-L2, there was a significant difference in the survival rate between subgroups according to the presence or absence of T-PD-L2 expression. CONCLUSIONS Our results suggest that I-PD-L2 expression is significantly correlated with favorable tumor behaviors and better survival rates. There is also a significant correlation between PD-L2 expression and PD-L1 expression in immune cells.