Objective To explore the clinical features, imaging features and treatment outcomes of renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion (Xp11.2/TFE3 RCC) in adult patients. Methods The clinical data of 43 adult patients with Xp11.2/TFE3 RCC confirmed by pathology from Sep. 2014 to Jul. 2019 in Changhai Hospital of Naval Medical University (Second Military Medical University) were collected. The general information, clinical symptoms, imaging data, surgical approaches, pathological data and prognosis of the patients were retrospectively analyzed. Results Among the 43 Xp11.2/TFE3 RCC cases, there were 24 males and 19 females, aged from 25 to 77 years, with an average age of (47.5±15.2) years. The main clinical manifestations included gross hematuria (five cases), lumbar and abdominal discomfort (six cases), and the symptom caused by tumor metastasis (one case); the other 31 cases were found during physical examination without obvious symptoms. The diameter of the tumor was 1.1-9.5 cm (average[5.1±2.7] cm). The lesions were round-like in 29 cases and irregular in 14 cases, and 37 cases had distinct borders and pseudocapsules around the tumors, six cases with poorly-defined borders. Most of the lesions showed heterogeneous changes in density or signal, mainly manifested as hemorrhage (21 cases), cystic degeneration or necrosis (24 cases) and calcification (11 cases). There were moderate to marked enhancement in 30 cases, mild enhancement in 13 cases, including papillary enhancement in 23 cases. Perirenal invasion appeared in 10 cases and distant metastases in eight cases. Among the 43 patients, 15 patients underwent laparoscopic radical nephrectomy, 13 patients underwent laparoscopic partial nephrectomy, seven patients underwent intelligent arm-assisted laparoscopic partial nephrectomy, five patients underwent open radical nephrectomy, one patient underwent open partial nephrectomy, one patient underwent renal biopsy, and one patient underwent resection of metastatic spinal canal tumor. The results of immunohistochemistry in 43 patients and fluorescence in situ hybridization in three patients were all positive for TFE3. High positive expression rates of carbonic anhydrase Ⅸ (CAⅨ; 74.4%, 32/43), avidin-biotin-peroxidase complex (ABC; 93.0%, 40/43), CD10 (93.0%, 40/43), von Hippel-Lindau (VHL; 72.1%, 31/43) and low-molecular-weight cytokeratin (CAM5.2; 83.7%, 36/43) were found through immunohistochemistry staining. The positive expression rate of Ki-67 ranged from 1% to 60%, with an average of 9.7%. Except for six patients who were lost to follow-up, the other 37 patients were followed up for 11-68 months, with an average of (47.4±17.5) months. During the follow-up period, five patients had multiple metastases, of which three patients died, and two patients had no significant progress after treatment with targeted drugs and were still alive; one patient had postoperative recurrence. Conclusion The main clinical manifestations of adult Xp11.2/TFE3 RCC patients are hematuria and umbar and abdominal discomfort. More patients are asymptomatic and found in physical examination. Imaging manifestations are diverse. The final confirmed diagnosis of Xp11.2/TFE3 RCC relies on pathological examination. Surgery, especially radical nephrectomy, is the first choice for Xp11.2/TFE3 RCC patients. Most patients have ideal prognosis, and a few patients have recurrence or metastasis after surgery.