Iron regulatory protein 2 (IRP2), a posttranscriptional regulator of iron metabolism, is subjected to iron-dependent degradation by the proteasome. Recent experiments proposed a mechanism involving 2-oxoglutarate-dependent oxygenases. Enzymes of this class, such as prolyl-4-hydroxylases, mediate the oxygen and iron-dependent degradation of the hypoxia inducible factor HIF-1alpha, which requires the E3 ubiquitin ligase activity of pVHL. Considering that the pathways for IRP2 and HIF-1alpha degradation share remarkable similarities, we investigated whether pVHL may also be involved in the degradation of IRP2. We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2. However, the iron-dependent degradation of endogenous IRP2 is not impaired in VHL-deficient cell lines, suggesting that pVHL is not a necessary component of this pathway.