Clear cell renal cell carcinomas (ccRCC) are characterized by inactivation of von Hippel-Lindau (VHL) gene and intracellular lipid accumulation by unknown pathomechanism. The immunochemical analysis of 356 RCCs revealed high abundance of apolipoproteins apoA-I and apoB as well as scavenger receptor BI (SR-BI) in the clear cell RCC subtype. Given the characteristic loss of VHL function in ccRCC, we used VHL-defective and VHL-proficient cells to study the potential influence of VHL on lipoprotein uptake. VHL-defective patient-derived ccRCC cells and cell lines (786O and RCC4) showed enhanced uptake as well as less re-secretion and degradation of radio-iodinated high and low density lipoproteins (125I-HDL and 125I-LDL) compared to the VHL-proficient cells. The ccRCC cells showed enhanced VEGF and SR-BI expression compared to normal kidney epithelial cells. Uptake of 125I-HDL and 125I-LDL by patient-derived normal kidney epithelial cells as well as VHL-re-expressing ccRCC cell lines 786-O-VHL and RCC4-O-VHL cells was strongly enhanced by VEGF treatment. The knock-down of VEGF co-receptor neuropilin (NRP1) as well as blocking of SR-BI significantly reduced the uptake of lipoproteins into ccRCC cells in vitro. LDL stimulated proliferation of 786-O cells more potently than 786-O-VHL cells in a NRP1- and SR-BI- dependent manner. In conclusion, enhanced lipoprotein uptake due to increased activities of VEGF/NRP1 and SR-BI promotes lipid accumulation and proliferation of VHL-defective ccRCC cells.