Background: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare type of RCCs with various fusion types and heterogeneous clinicopathological features. MED15-TFE3 is a fusion that usually present as an extensive cystic mass with low malignant potential. We sought to summarize the clinicopathological, transcriptomic characteristics and survival outcome in MED15-TFE3-rRCC patients. Methods: All 14 cases were collected retrospectively fromSichuan University West China Hospital from 8/2011 to now. Diagnosis of MED15-TFE3 fusion was confirmed by fluorescence in situ hybridization and RNA sequencing. The clinicopathological features and follow-up data were collected for further analysis. The tumor transcriptomic profiles were analyzed by Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis via R tool. Results: The median age was 43.5 years (range, 22 to 70). Majority of the cases were female (10/14). 8 patients (57.1%) underwent radical nephrectomy, 1 patient received cytoreductive surgery, and 5 patients (35.7%) received partial nephrectomy. At initial diagnosis, most cases (10/14) were localized disease, while 2 patients had regional lymph nodes metastasis, and 1 patient had distant metastasis (bone). For the patients without distant metastasis (n=13), 2 patients developed metastasis (liver, lung, abdominal, in situ) with disease-free survival of 11.4 and 29.0 months. As for the pathological features, 10 (71.4%) of thesamples presentedcystic morphologically, and other 4 (28.6%) were papillary. 10 (71.4%) were in G2 by ISUP score. For metastatic patients, 3 received first-line therapy (1 axitinib, 1 axitinib + sintilimab, 1 sunitinib), 2 received second-line therapy (1 axitinib + sintilimab, 1 axitinib + toripalimab), 1 received third-line therapy (axitinib + toripalimab + everolimus). They are still under follow-up. GSEA analysis illustrated that compared to paraneoplastic tissue, apical surface, bile acid metabolism, KRAS signaling, Xenobiotic Metabolism, and estrogen response were upregulated in tumor. For the patients with distant metastases, the transcriptomic analysis revealed that organelle fission, nuclear division, mitotic nuclear division, and chromosome segregation were significantly upregulated, which may be associated with tumor metastasis. The overall immune cell infiltration was comparable in metastatic patients and non-metastatic patients. However, the expression level of type 17 T helper cell, B cells, plasmacytoid dendritic cell, and activated dendritic cell were significantly different. Conclusions: MED15-TFE3 rRCC mainly present low-grade cystic renal neoplasm with favorable prognosis. For metastatic MED15-TFE3 rRCC, there is no standard therapy. And the transcriptomic evidence may provide insights for future research.