Programmed cell death-1/ligand (PD-1/PD-L1) interaction negatively regulates T cell activity. PD-L1 expression in tumor cells, antigen-presenting cells, and lymphocytes of the tumor microenvironment is associated with response to treatment with PD-1/PD-L1 inhibitors, but there is still debate on the cutoff value that correlates with responders. In uveal melanoma (UM), 40% of patients will develop liver metastases and, amongst them, 90% will succumb to their disease. The aim of this study was to analyze PD-L1 expression as a prognostic marker and as a possible therapeutic target for UM. Sixty-seven enucleated eyes from UM patients with relevant clinical information were analyzed. Univariate and multivariate analysis were used to evaluate association of PD-L1 with survival. PD-L1 expression was positive relatively to tumor cells, immune cells, and the tumor and tumor-infiltrating immune cell group scoring in 46, 34 and 55% of the cases, respectively. On univariate analysis, tumor cells and the tumor and tumor-infiltrating immune cell group PD-L1 expression was associated with a longer metastasis-free survival (P = 0.04 and P = 0.007). However, on multivariate analysis, only the tumor and tumor-infiltrating immune cell group positivity was associated with longer metastasis-free survival (P = 0.01). Furthermore, tumor cells and the tumor and tumor-infiltrating immune cell group PD-L1 expression was associated with decreased tumor-infiltrating lymphocytes (P = 0.02). PD-L1, when expressed in uveal melanoma, is associated with better patient outcome and decreased tumor-infiltrating lymphocytes. These results support the consideration of anti-PD-1/PD-L1 therapy in uveal melanoma. To determine the best cutoff value, further studies from patients enrolled in clinical trials treated with PD-1/PD-L1 inhibitors are necessary.