Reptin is an AAA+ ATPase associated with several complexes involved in chromatin remodeling, transcriptional regulation, DNA damage repair, and telomerase activity. Functional studies have implicated reptin in many cellular processes highly relevant to cancer. In this study, we investigated reptin expression in renal cell carcinoma (RCC) and its biologic functions in RCC cells.A total of 81 RCC patients were involved in the study. Cancerous and adjacent normal renal tissues were analyzed for reptin expression using immunohistochemistry. Univariate association with survival was evaluated using Kaplan-Meier curves. Gene expression was depleted with specific small interference RNA. Clonogenesis, cellular senescence, and cell cycle distribution were examined by foci formation, β-galactosidase staining, and flow cytometry, respectively. Cell migration and invasion capability were determined by scratch migration assay and Matrigel invasion assay.Reptin is overexpressed in cancerous tissues compared with tumor adjacent renal tissues. Cytoplasmic expression of reptin positively correlates with the poor differentiation of RCC, and predicts an unfavorable outcome for patients. Depleting reptin expression substantially inhibited clonogenic potential of cancer cells and induced senescence of RCC cells. Moreover, reptin depletion attenuated migration and invasion ability of RCC cells in vitro.Reptin is overexpressed and aberrantly distributed in RCC. It is required for sustained proliferation of cancer cells by preventing cell growth arrest and senescence. Furthermore, reptin promotes cell migration and invasion, which may contribute to the progression of RCC. Therefore, reptin may prove to be a valuable target for prevention and treatment of renal cell carcinoma.