The von Hippel-Lindau (VHL) tumor suppressor gene has a critical role in the pathogenesis of clear cell renal cell carcinoma (RCC), because VHL mutations have been found in both VHL disease-associated and sporadic RCC. Overexpression of transforming growth factor (TGF)-α has been observed in numerous RCC tumors and cell lines, and TGF-α has been demonstrated to support RCC cell growth through an autocrine loop. We demonstrate here that VHL substantially decreases TGF-α message and protein by shortening TGF-α mRNA half-life. By Northern analysis TGF-α mRNA steady-state levels were suppressed 5-fold in permanent 786-0 RCC cell lines expressing wild-type VHL compared with 786-0 cells expressing an empty vector or a mutant VHL protein lacking COOH-terminal residues 116–213 (ΔVHL). By Western analysis, VHL also substantially down-regulated the unprocessed, cell-associated M_r 20,000 TGF-α protein. Moreover, secreted TGF-α was undetectable in VHL-expressing cells. In contrast, VHL did not down-regulate the TGF-α receptor, epidermal growth factor receptor, either at the mRNA or protein level. Nuclear run-on in vitro transcription experiments in 786-0 cells showed that VHL did not affect transcriptional control of the endogenous TGF-α gene. However, actinomycin D experiments revealed a long TGF-α mRNA half-life in 786-0 cells that was significantly decreased by wild-type VHL but not by ΔVHL. We have, therefore, identified TGF-α, an important growth factor for RCC, as a new target gene for VHL and demonstrated that VHL acts by decreasing TGF-α mRNA stability.