Mass spectrometry analysis of renal cancer cell lines recently suggested that the Protein-Tyrosine Phosphatase Receptor Type J (PTPRJ), an important regulator of tyrosine kinase receptors, is tightly linked to the von-Hippel Lindau protein (pVHL). Therefore, we aimed to characterize the biological relevance of PTPRJ for clear cell renal cell carcinoma (ccRCC). In pVHL negative ccRCC cell lines both RNA and protein expression levels of PTPRJ were lower than those in the corresponding pVHL reconstituted cells. Quantitative RT-PCR and Western blot analysis of ccRCC with known VHL mutation status and normal matched tissues as well as RNA in situ hybridization on a Tissue Microarray (TMA) confirmed a decrease of PTPRJ expression in more than 80 % of ccRCCs, but in only 12 % of papillary RCCs. ccRCC patients with no or reduced PTPRJ mRNA expression had a less favourable outcome than those with a normal expression status (p = 0.05). Sequence analysis of 32 PTPRJ mRNA negative ccRCC samples showed five known polymorphisms, but no mutations implying other mechanisms leading to PTPRJ's down-regulation. Selective silencing of HIF-α by siRNA and reporter gene assays demonstrated that pVHL inactivation reduces PTPRJ expression through a HIF-dependent mechanism, which is mainly driven by HIF-2α stabilization. Our results suggest PTPRJ as a member of a pVHL controlled pathway whose suppression by HIF is critical for ccRCC development. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.