Abstract Purpose: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. Results: In the training cohort (n = 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P < 0.001), Gleason score (P = 0.004), and androgen receptor (AR) expression (P < 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P = 0.004; HR, 2.37; 95% confidence interval (CI), 1.32–4.25]. In the test cohort (n = 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P = 0.011; HR, 1.49; 95% CI, 1.10–2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P < 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P = 0.007; HR, 1.46; 95% CI, 1.11–1.92). Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1–targeted therapy might be a treatment option for hormone-naïve prostate cancers. Clin Cancer Res; 22(8); 1969–77. ©2015 AACR.