Background: Prostate adenocarcinoma is the second most commonly occurring cancer in men, yet therapeutic progress in the past decade has stalled. Immune checkpoint inhibitors (ICI) are being successfully used for the treatment of multiple types of cancers and remain an appealing treatment option for patients with prostate adenocarcinoma. Unfortunately, only a small group of patients with prostate cancer appear to benefit from treatment with ICI. Both HLA-DR and PD-L1 have been identified as predictors of response to ICI in other malignancies. We investigated the prevalence of HLA-DR and PD-L1 expression in prostate cancer, and if there is a correlation with clinical characteristics. Methods: For this retrospective cohort study, 40 patients were randomly selected from a database of patients with prostate cancer seen at the Washington DC VA Medical Center between 2000 and 2022; 19 patients (47.5%) with metastatic disease at presentation and 21 patients (52.5%) presenting without metastatic disease. Clinical information was collected and included age at diagnosis, ethnicity, PSA at diagnosis, total Gleason score, and AJCC stage. Tissue samples of the primary tumors were retrieved and immunohistochemistry was performed for HLA-DR and PD-L1. Staining was independently scored by two experienced pathologists who were blinded to clinical information. Results: HLA-DR was found to be expressed in 14 patients (35%) with prostate cancer, whereas PD-L1 positivity was identified in 18 patients (45%). HLA-DR expression was not associated with metastatic disease, PSA at diagnosis, Gleason score, or AJCC stage (p = 0.816, p = 0.314, p = 0.920,p = 0.458, respectively). In contrast, PD-L1 positivity was significantly associated with metastatic disease (p = 0.028), a higher PSA at diagnosis (p = 0.041), Gleason score (p = 0.026), as well as AJCC stage (p = 0.0438). No correlation was observed between HLA-DR positivity and positivity for PD-L1 (p = 0.641). Conclusions: Both HLA-DR and PD-L1 are found to be expressed in tumor tissues of patients with prostate adenocarcinoma. Although HLA-DR expression was not associated with clinical characteristics, we did observe an association between PD-L1 positivity and advanced disease. This observation would be consistent with prior studies that have reported that PD-L1 expression in prostate cancer is correlated with clinic-pathologic features such as advanced stage of disease, castration resistance and poor overall survival. More studies are necessary to evaluate if PD-L1 could serve as prognostic or predictive biomarker in prostate adenocarcinoma.