Background: Immune Checkpoint Inhibitors (ICIs), either as monotherapy or in combination with tyrosine kinase inhibitors (TKIs), were recently incorporated into the therapeutic guidelines for recurrent/metastatic endometrial cancer (EC). Microsatellite Instability (MSI) is the only biomarker to guide treatment. We evaluated the predictive significance of Estrogen Receptor (ER) and p53 expression. Methods: Medical charts of EC patients that received ICIs in our institution for advanced/metastatic disease were retrospectively reviewed. TP53 and ER expression were determined by immunohistochemistry. Survival analysis was performed using IBM SPSS statistics v.25. Results: Thirty-two patients were included in our analysis. The median age was 63.1 years (25^th-75^th percentile: 57.6 – 69.6). 62.5% of the patients had endometrioid histology, 21.9% serous histology and 15.6% of them displayed other histology. 46.9% of the patients had grade 1-2 tumors and 53.1% grade 3 tumors. 21.9% of them were diagnosed with stage 1-2 disease, while 78.1% presented with stage 3 disease. 62.5% received 0-1 prior lines of treatment and 37.5% of them received more than 2 prior lines. Molecular characteristics are presented in the table. All MSI-High patients received anti-PD1 monotherapy with a median PFS of 11.9 months (95% CI:2.3-21.5). Microsatellite Stable (MSS) patients received pembrolizumab-lenvatinib combination with median PFS 7.54 months (95% CI:2.6-11.5). ER positivity was associated with significant PFS benefit in both the ICI monotherapy group (11.9 vs. 0.63 months, p=0.061) and the group that received ICI/TKI combination (11.3 vs. 1.75 months, p=0.001). Analogous benefit was noted in the Overall Survival post start of IO or IO/TKI treatment (9.8 vs 0.6 months in MSI-high patients and 20.6 vs 5.9 months in MSS patients). ER-positivity remained an independent predictive factor favoring PFS in the Multivariate Cox regression analysis when adjusting for immunotherapy type, histology, and previous lines of therapy (HR=0.216, p=0.013). Conclusions: ER expression proved to be an independent prognostic factor regarding PFS in our cohort of patients. Further studies are needed to investigate the role of ER as a predictive biomarker for immunotherapy in EC.