Background: PEComa is a rare mesenchymal neoplasm composed of perivascular epithelioid cells. Due to its rarity, diagnosis is challenging and no standardized treatment guidelines have been established. A subgroup of PEComas are characterized by a loss of function mutation in TSC1/2 that activates the PIK3-Akt-mTOR pathway. In the majority of patients, however, the molecular landscape and the composition of the tumor microenvironment (TME) remain largely unclear. Thus, we conducted this study to elucidate the genetic landscape of PEComas. A comparative analysis was performed with melanoma as a representative immunogenic tumor type. Methods: Thirty-five PEComa specimens were centrally analysed at the Caris Life Sciences laboratory. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome-sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression profiling (GEP) was performed by unsupervised hierarchical clustering. RNA deconvolution analysis was performed using the Microenvironment Cell Populations (MCP)-counter method to quantify immune cell populations (Becht 2016, Genome Biology). Results: The most common mutations detected in this cohort were TP53 (47%), ATRX (32%), TSC1/2 (11%/29%) and MSH3 (17%). Interestingly, TP53 mutations occurred less frequently (25 vs 60%, p = 0.055) in TSC1/2-mutated (TSC1/2-mt) compared to TSC1/2-wildtype (TSC1/2-wt) tumors, whereas MSH3 (25%, n = 1/4) and ERCC2 (14%, n = 2/14) mutations were exclusively observed in TSC1/2-mt cases. TSC1/2 mutations and other mTOR signalling pathway alterations, including two TFE gene fusion transcripts, were mutually exclusive. Of note, we found that 33.3% (n = 2) of TSC2-mt tumors were associated with high PIK3-Akt-mTOR pathway expression, while 100% (n = 3) of TSC1-mt tumors demonstrated lower expression. Deficient mismatch repair/microsatellite instability-high and high tumor mutational burden were rare (2.9%, n = 1 each) and observed concurrently in absence of PD-L1 expression. Overall, PD-L1 expression was observed in 21.9% (n = 7) of patients. An exploratory comparison with melanoma revealed that PEComa TMEs were characterized by a significant increase of NK cells and fibroblasts, as well as a relevant decrease of CD8⁺ T cells and B cells. Conclusions: Within this study we discovered a heterogeneous molecular landscape with a high prevalence of TSC1/2 mutations that were in part associated with transcriptional up-regulation of the PIK3-Akt-mTOR pathway. Furthermore, the relatively immune-cold TME compared to melanoma suggests increased lymphocyte infiltration may be required to increase the efficacy of immune checkpoint inhibitors for PEComa.