Background: Uterine carcinosarcoma (UCS) is subtype of endometrial cancer (EC) with aggressive behavior and poor prognosis. UCS has not traditionally been included in EC clinical trials and treatment options are limited. Immune-oncology (IO) therapy has shown promise UCS, but it is unknown which patients benefit most. We sought to identify immunogenic markers in UCS and explore treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be <0.05. Results: A total of 1,144 UCS tumors underwent comprehensive tumor profiling. 68.4% of samples were obtained from primary tumors and 31.6% from metastatic sites. 21.6% of tumors expressed PD-L1, 8.5% were TMB-H and 6.8% were MSI-H/MMRd. UCS patients treated with IO had longer median overall survival than those not treated with IO (months: 31.2 vs 19.4; HR(95% CI): 0.39 (0.17-0.76) p=0.005). Median OS was also increased for dMMR/MSI-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.56 (0.36-0.92) p=0.019) and TMB-H (OS not yet reached vs 18.9 months); HR(95% CI): 0.62 (0.38-0.99) p=0.047). More patients are needed to determine if these markers predict response to IO therapy. The most common mutations in UCS led to pathway dysregulation in the PI3K, RAS, chromatin remodeling, HR, and WNT pathways. dMMR/MSI-H tumors have distinct molecular profiles compared to MSS tumors (table). Additionally, dMMR/MSI-H tumors had higher TMB (96.9% vs 2.2%, q<0.01) and increased frequency of PDL-1 (23.6% vs 13.8%; q=0.04). Immune checkpoint genes were more often expressed in MSI-H tumors, though this was non-significant except for IFNG (4.66-fold increase; q=0.01). Conclusions: IO therapy is associated with improved survival in USC. MSI and TMB are markers of improved OS in patients with UCS. MSI tumors have a distinct molecular profile compared to MSS tumors, and they appear to be more immunogenic, which could contribute to the improved survival seen in patients who received IO therapy.