<b><i>Purpose:</i></b> Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa. <b><i>Patients and Methods:</i></b> Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC­oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab. <b><i>Results:</i></b> All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8–76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in <i>TSC2</i> 32.3% of cases (10), <i>TSC1</i> 9.6% (3), <i>TFE3</i> 16.1% (5, all fusions), and folliculin (<i>FLCN</i>) 6.4% (2), with all occurring in mutually exclusive fashion. Of <i>TSC2</i> mutant cases, 70% had biallelic inactivation of this locus, as were 100% of <i>TSC1</i> mutant cases. Two <i>TSC1/2</i> wildtype cases harbored truncating mutations in <i>FLCN</i>, both of which were under LOH. Five <i>TFE3</i> fusion cases were identified including the novel 5′ fusion partner <i>ZC3H4</i>. <b><i>Conclusions:</i></b> We describe for the first time mPEComa cases with <i>FLCN</i> mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC­oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by <i>TSC</i>, <i>TFE3</i>, and <i>FLCN</i> status via CGP in clinical care.