The solubility of cholesterol (Ch) in quaternary mixtures of bile salt (BS), lecithin (L), inorganic salt (Ca2+), and water, which can be used as model biles was measured at 310.2 K in this work. The accurate concentrations of bile salt, lecithin, and cholesterol were determined by high performance liquid chromatography (HPLC). The effect of bile salt/lecithin molar ratio, bile salt concentration, total lipid concentration, and Ca2+ concentration on the solubility of cholesterol were investigated in detail. The results show that the cholesterol solubility monotonically increases with the increase of the concentration of bile salt or total lipid. The cholesterol solubility first increases with the bile salt/lecithin molar ratio when the bile salt/lecithin molar ratio is lower than 1 and then decreases when the bile salt/lecithin molar ratio further increases. In addition, the existence of Ca2+ in the model biles will significantly decrease the solubility of cholesterol.