Background: While renal AML is generally a benign tumor, malignant eAML is a rare form of renal malignancy of uncertain histogenesis featuring variable prognosis. Consequently, most series are limited in small sample sizes and lack comprehensive genomic analysis. We sought to survey the genomic landscape in malignant renal eAML and identify potential therapeutic targets. Methods: After reviewing our database containing over 400,000 advanced cancer samples we identified 34 cases of malignant eAML. Comprehensive genomic profiling (CGP) was performed using a hybrid capture technique to assess all classes of genomic alterations (GA). MSI status, gLOH, genomic ancestry and gene signatures were determined by CGP. TMB was measured in mutations/megabase of sequenced DNA. PD-L1 positivity was determined by IHC using the DAKO 22C3 tumor cell proportional score (0% = negative; 1-49% = low positive). Results: The primary malignant eAML was used for CGP in 14/34 (41.2%) and a metastatic site biopsy was used in 20 (58.8%) cases (10 liver, 3 lung, 4 retroperitoneum, 2 peritoneum and 1 psoas muscle). There were 19 (55.9%) female patients and a mean age of 60 years (median 53 years). In a subset 17 of cases when either MART1, MelanA or HMB45 IHC staining was performed all cases were positive for at least 1 marker. There were no MSI-high cases. The mean and median TMB was 1.6 mutations/Mb. Of the 4 malignant eAML cases tested, 3 (75%) were negative and 1 (25%) case was low PD-L1 expression positive. 25 (73.5%) of the cases featured short variant mutations in the TSC2 gene while the other 9 (26.5%) were TSC2 mutation negative. 4 (11.8%) of the malignant eAML featured germline GA in the MUTYH, CD36, FLCN, and FANCC genes of uncertain roles in the development of the disease. There were no TSC2 germline GA. Other GA were mostly not currently targetable and included the tumor suppressors TP53 at 29.4%, CDKN2A/B at 14.7%, ATRX at 11.8%, and RB1 at 8.8%. Aside from the frequent TSC2 alterations, other GA potentially implicating MTOR inhibitor use include GA in PTEN at 5.9% and NF2 at 2.9%. Additionally, BRCA1 was altered in 2.9% of cases, suggesting the possible utility of a PARP inhibitor. In a 28 case subset, the mean gLOH was 6.3% (range 0% to 37.9%) with 3 cases (10.7%) featuring a gLOH of > 16%. 26 (76.5%) of these patients were of EUR ancestry, 5 (14.7%) of AMR ancestry and 3 (8.8%) of AFR ancestry. No specific genomic signature characterized the malignant eAML cases. Conclusions: Renal malignant eAML, also known as malignant PEComa of the kidney, is an exceedingly rare malignant tumor. Our CGP identified that the majority of cases exhibit non-germline TSC2 mutations. Interestingly, other germline alterations were found in 4/34 cases which are of unknown significance. While there may be limited opportunities for targeted or immunotherapies aside from MTOR inhibition, CGP analysis may still provide guidance into identification of potential therapeutic targets.