Background: TCGA identified two groups of endometrial cancers with high mutation frequency: an ultramutated group of tumors which harbored mutations in polymerase e (POLE) and a hypermutated group with microsatellite instability (MSI). We hypothesized that these hypermutated tumors may harbor more neoantigens and thus stimulate a stronger immune response compared to tumors with low mutation frequency. In this regard, we evaluated whether hypermutated tumors are associated with an elevated number of tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocytes and higher expression of the immune modulatory molecule PD-L1. Methods: We evaluated 4 POLE-mutated (determined via Sanger sequencing of mutational hotspots), 28 MSI-tumors and 32 microsatellite stable (MSS) endometrioid endometrial tumors. MSI status was determined using immunohistochemistry (IHC). IHC was performed for CD3, CD4, CD8, CD20, PD-1 and PD-L1 using standard protocols. For evaluation of TILs, a photomicrograph (40X) of the area of maximum CD3+ intraepithelial lymphocytes was obtained with corresponding photomicrographs for the additional stains. For peritumoral lymphocytes, a semi-quantitative scoring method was utilized. Results: POLE-mutated and MSI tumors exhibited significantly elevated CD3+ (p = 0.001), CD4+ (p = 0.078) and CD8+ (p < 0.001) TILs compared to MSS tumors. CD20+ TILs were not statistically significantly different between MSI/POLE tumors and MSS tumors. Expression of PD-1 (p < 0.001) and PD-L1 (p = 0.022) was higher in TILs of POLE and MSI tumors compared to MSS tumors. Furthermore, POLE and MSI tumors harbored more peritumoral T-lymphocytes (p < 0.001) and higher expression of PD-1 (p = 0.001) and PD-L1 (p < 0.001) compared to MSS tumors. There were no significant differences in TILs, peritumoral lymphocytes and PD-1/PD-L1 expression between POLE-mutated and MSI tumors. Conclusions: POLE-mutated and MSI endometrial cancers are associated with an elevated number of TILs and peritumoral lymphocytes, and higher expression of PD-1 and PD-L1. These data support trials of immune-checkpoint inhibitors in hypermutated endometrial cancers.