Alternative models exist explaining the biliary lipid secretion at the canalicular membrane of hepatocytes: Successive lipid extraction by preformed bile salt micelles or budding of membrane fragments with formation of mixed micelles. To test the feasibility of the latter mechanism, we developed a mathematical model that describes the formation of lipid microdomains in the canalicular membrane. Bile salt monomers intercalate into the external hemileaflet of the canalicular membrane, to rim liquid disordered domain patches which then pinch off to form nanometer-scale mixed micelles. Model simulations perfectly recapitulate the measured dependence of bile salt-dependent biliary lipid extraction rates at varying membrane content of cholesterol (lack/overexpression of the cholesterol transporter Abcg5/g8) and phosphatidylcholine (lack of mdr2). The model reveals a strong dependence of the biliary secretion rate from the protein density of the membrane. Taken together, the proposed model is consistent with crucial experimental findings in the field and provides a consistent explanation of the central molecular processes involved in bile formation.