We investigated the role of protein tyrosine phosphatase zeta (Ptprz1) in human renal cell carcinoma (RCC) cells' proliferation and associations between Ptprz1 expression and von Hippel-Lindau (VHL) activation. A normal human renal cell line and four human RCC cell lines were used in this study. VHL or Ptprz1 expression in RCC cells was increased by transfection with a VHL or Ptprz1 vector. VHL or Ptprz1 expression was decreased in these cells by siRNA using Lipofectamine 2000. Cells' proliferative activity was assessed by WST-1 assay. Our results suggested that Ptprz1 was a target of VHL, and a loss of VHL activation increased Ptprz1 expression in RCC cells. Ptprz1 enhanced beta-catenin protein expressions in the nuclear fractions of RCC cells and participated in regulating proliferation by activating beta-catenin and its downstream genes. In addition, a loss of VHL activity may enhance the proliferative activity of RCC cells by increasing Ptprz1 expression. Ptprz1-enhanced RCC cells' proliferation depends on VHL inactivation, and the Ptprz1/beta-catenin pathway may be a potential target for treating RCC with inactive VHL.