Background: Recent data has shed light on molecular profiles of uterine carcinosarcoma (UCS), but few have correlated molecular profiles with prognosis. In a preliminary data analysis, we found that hormone receptors (HR)—estrogen receptor (ER) and progesterone receptor (PR)—expression was associated with improved OS. Here, we investigate the molecular profile differences between ER+/- and PR +/- tumors. Methods: Tumor samples were analyzed using Next-Generation sequencing of DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) at the Caris Life Sciences Laboratory (Phoenix, AZ).ER and PR tested by IHC on whole tumor (cut-off: +1, 10%). PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC an 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 cohorts. Statistical significance was determined by chi-square and Wilcoxon rank sum test and p-values adjusted for multiple comparisons (q) to be <0.05. Results: 1,144 UCS tumors were included. (ER+, n=261; PR+, n=197; HR+ (ER+ and PR+), n=168). Median OS for patients with hormone receptor (HR)+ tumors was significantly longer than for patients with HR- tumors (months: 34.8 vs 17.4; HR(95% CI): 0.67 (0.53-0.84), p<0.01). This remained significant for ER (29.4 vs 17.3) and PR (25.3 vs 18.7) individually. ER+ tumors had fewer alterations in the TP53 pathway (71.4% vs 82.1%) in the WNT (19.5% vs 5.8%) pathway than ER- tumors (q<0.05). PR+ tumors had similar findings in the TP53 and WNT pathways, and also more alterations in the DNA damage sensor pathway. Both ER+ and PR+ UCS tumors had significantly increased MSI-H (ER: 10.9% vs 5.5%, PR: 12.9% vs 5.5%) and TMB-H (ER: 16.8% vs 6.0%; PR: 19.5% vs 6.1%) (all q<0.05) compared to ER- and PR- tumors. They also had increased T-reg cells in their immune micro-environment and increased expression of the immune checkpoint gene IDO1 (q<0.05; Table). Conclusions: HR+ tumors have distinct molecular profiles from HR- tumors. ER+ and PR+ UCS tumors appear more immunogenic with more frequent MSI-H status, TMB-H, increased infiltrating regulatory T-cells and IDO1 expression, suggesting possible benefit with immune-oncology (IO) therapy. This may contribute to the observed improved OS, but more data are needed to determine if HR status is a marker of response to IO therapy.