Objective: Histone deacetylase (HDAC) is a tumor suppressor gene in various carcinomas; however, the effect of HDAC10 on human renal cell carcinoma (RCC) remains unknown. In the current study we analyzed the expression and function of HDAC10 in human clear cell RCC. Methods: RCC tissues from 145 patients who underwent radical nephrectomies were evaluated. HDAC10 protein and mRNA expression was examined by immunohistochemistry and quantitative RT-PCR, respectively. HDAC10 expression was increased by stable transfection with a vector containing full-length cDNA of HDAC10, and HDAC10 expression was decreased by siRNA in two RCC cell lines. Proliferation analysis of RCC cells in vitro was investigated using the WST-1 assay, and the invasion assay was performed using a 24-well Transwell chamber. The phosphorylation of beta-catenin induced by HDAC10 was evaluated by Western blot. Results: HDAC10 expression in RCC tissues was significantly down-regulated compared to normal kidney tissues. Moreover, the low level of HDAC10 expression was uniformly associated with advanced clinical stage, larger tumor diameter, higher pathologic grade, and metastatic RCC. In addition, decreased expression of HDAC10 significantly prompted the proliferation and invasion of RCC cells in vitro. Although HDAC10 did not regulate the expression of beta-catenin, HDAC10 suppressed the phosphorylation of beta-catenin in RCC cells. Conclusions: HDAC10 expression is suppressed in human clear cell RCC and is involved in development and metastasis of RCC. The findings herein suggest that HDAC10 is an independent predictive factor for RCC prognosis, and restoring HDAC10 expression may be a new therapeutic strategy for advanced RCC.