Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. One of the pathological drivers for ccRCC is the Ras family of small GTPases that function as “molecular switches” in many diseases including ccRCC. Among the GTPases in the Di-Ras family, DIRAS2 gene encodes a GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2 or how its activities are regulated. In this study, we focused on Di-Ras2, and determined its functions and underlying mechanism during formation of ccRCC. We found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau protein (pVHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, pVHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene in ccRCC, and these data provide a new perspective of the relationship between pVHL and the MAPK pathway in ccRCC tumorigenesis.