The von-Hippel Lindau tumor suppressor protein (pVHL) is conserved throughout evolution, as its homologues are found in organisms ranging from mammals to the Drosophila melanogaster and Anopheles gambiae insects and the Caenorhabditis elegans nematode. Although the physiological role of pVHL is not fully understood, it has been shown to interact with a large number of unrelated proteins and was suggested to play a role in protein degradation as an E3 ubiquitin ligase component in the ubiquitin pathway. To gain insight into the molecular basis of pVHL activity, we analyzed its folding and stability in solution under physiologically relevant conditions. Dynamic light-scattering and gel filtration chromatography of the purified pVHL clearly indicated that the Stokes radius of the protein is larger than what would be expected from its crystal structure. However, under these conditions, the protein shows a clear secondary structure as determined by far-UV circular dichroism. Yet, the near-UV CD experiments show an absence of a tertiary structure. Upon the addition of urea, even at very low concentrations, the protein unfolds in a non-reversible manner, leading to the formation of amorphous aggregates. Furthermore, a large increase in fluorescence (>50-fold) is observed upon the addition of pVHL into a solution containing 8-anilino-1-naphthalene sulfonic acid. We therefore conclude that, under native conditions, the non-bound pVHL has a molten globule configuration with marginal stability. Although molten globular structures can be induced in many proteins under extreme conditions, this is one of the few reported cases of such a structure under the physiological conditions of pH, ionic strength, and temperature. The significance of the pVHL structural properties is being discussed in the context of its physiological activities.