Abstract: A novel approach is described for reversing aggregation and increasing refolding by application of hydrostatic pressure. A protein of interest in an aggregated, or inclusion body, or other non-native or inactive state is subjected to high hydrostatic pressure. This treatment denatures the protein to states (or conformations) competant for refolding and results in increased formation of native protein once pressure is released. The technique can facilitate conversion non-native proteins, including inclusion bodies and aggregates to native proteins without addition of chaotropic agents, changes in buffer, or large-scale dilution of reagents required for traditional refolding methods.