Hypoxia is a nearly ubiquitous characteristic of solid tumors. To determine whether HIF-dependent regulation of PGC-1alpha is intact in VHL wild-type cells exposed to low oxygen tensions, expression of PGC-1a protein and mRNA was compared in cell lines cultured in normoxia or hypoxia. Consistent with the results in VHL-deficient cells, hypoxia suppressed PGC-1alpha protein and mRNA levels in both non-transformed HK2 proximal tubule cells and in VHL wild-type TK10 ccRCC cells. When compared to normoxia counterparts, knockdown of HIF-1alpha blunted the decrease in PGC-1alpha mRNA and protein in cells exposed to hypoxia, indicating that this effect was HIF dependent. Similarly, HIF-alpha stabilization induced by treatment with the prolyl hydroxylase inhibitor dimethyloxaloyl-glycine (DMOG) resulted in HIF-1alpha-dependent suppression of PGC-1alpha mRNA.