Dilution induces structural alterations (i.e., vesicle formation) in the lipid particles of supersaturated human hepatic bile and in dilute model bile systems of comparable composition. These alterations strikingly increase both the degree and duration of metastable supersaturation. Concentrated normal human gallbladder bile also shows an increased but less striking degree and duration of metastability compared to comparable model biles. These differences, particularly with respect to gallbladder bile, cannot be attributed solely to compositional or lipid structural differences between native and model systems. They imply that additional factors are responsible for metastability. Furthermore, recent data suggest that biliary proteins may be involved. A limited number of these unidentified proteins have been shown to have the capacity to prolong metastability in supersaturated in vitro model systems. Thus, these recombined systems more nearly resemble the behavior of native bile. The mechanism of the nucleation inhibitory effect of these proteins is not clearly established.