Background: Clear cell carcinomas (CCC) are histologically similar, however their clinical course varies widely based on the organ of origin. Clear cell uterine carcinoma (CCUC) accounts for approximately 5% of endometrial carcinomas and exhibit aggressive clinical behavior with poor outcomes. Clear cell ovarian cancers (CCOCs) are a subtype of epithelial ovarian cancers that are chemo-resistant with a poorer prognosis than other subtypes. 70% of renal cell carcinomas are clear cell (CCRCs), and respond to TKIs and mTOR inhibitors. It’s unknown if these CCC rely on similar molecular pathways. Tumor profiling was used to identify subsets of CCC that may benefit from different therapies. Methods: 139 CCUCs, 409 CCOCs and 94 CCRCs were tested using a commercial multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Specific tests performed included sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH or FISH). Results: CCUCs had more TP53 mutations than CCOCs and CCRCs (40% vs 16% vs 14%). Compared to CCUCs and CCOCs, CCRCs had fewer mutations in the mTOR pathway (PIK3CA – 4% vs 25% vs 40%; PTEN - 1% vs 26% vs 3%) and the MAPK pathway (KRAS – 0% vs 14% vs 11%). VHL mutations were only seen in CCRCs (47% vs 0% vs 0%). ER and PR overexpression was more common in CCUCs than CCOCs and rare in CCRCs (ER – 35% vs 8% vs 0%; PR – 22% vs 13% vs 2%). AR overexpression was more common in CCRCs (26% vs 7% vs 5%). In contrast to CCUC and CCOC, no Her2 alterations measured by IHC, ISH or SEQ were seen in CCRCs.TOP2A, TS and RRM1 were expressed at a higher rate in CCUCs and CCOCs than CCRCs (TOP2A – 81% vs 63% vs 27%; TS - 46% vs 51% vs 16%; RRM1 – 22% vs 19% vs 2%). All CCC types had some immune-positivity for PD-1 (73%,47%, 68%) or PD-L1 (13%, 6%,29%). Conclusions: While CCUCs and CCOCs share similarities, the molecular profiling shows significant differences compared with CCRCs. This data suggest blockade of the mTOR and/or MAPK pathways may be important in CCUCs and CCOCs. Further, anti-angiogenic agents are more likely to be of benefit in CCRCs. Immunotherapies warrant further investigation in selected CCC patients. Future studies are needed to correlate these markers with sensitivity to chemotherapy.