The thermodynamic activity, A(T), of cholesterol (Ch), rather than the Ch saturation index (CSI), is the more appropriate measure of Ch supersaturation in bile. CSI has been based on the simple concept that the tendency for Ch dissolution or precipitation in bile should be directly related to the ratio of the actual Ch concentration to the equilibrium Ch solubility in bile. CSI, however, becomes inadequate when Henry’s law breaks down. In the present study, data on Ch uptake into silicone polymer films were used to quantify A(T) in Ch-supersaturated taurocholate (TC)-lecithin (L) solutions. Quasielastic light scattering (QLS) experiments were conducted to quantify the nature of lipid particles (micelles and vesicles) and, together with microscopic observations, to determine Ch nucleation times. The results from the A(T) Measurements, QLS measurements, and microscopic observations showed (a) that vesicles may be catalytic sites for Ch crystallite nucleation, (b) that mesophase formation may be a common occurrence in moderately supersaturated biles, and (c) that, at the same CSI, supersaturated systems with higher TC:L ratios require a higher A(T) for mesophase (vesicle) formation and have much shorter Ch nucleation times than those with lower TC:L ratios.