The contribution of dispersion and digestion in the stomach to the bioavailability of poorly water-soluble drugs administered in lipid-based formulations was assessed by comparison of intraduodenal (ID) and peroral (p.o.) administration using cinnarizine (CZ) as a model drug. Differences in the dispersion and digestion in the gastric and intestinal compartments for medium-chain triacylglycerides (MCT) and long-chain triacylglycerides (LCT) were observed, leading to differences in the oral bioavailability of CZ. Bypassing gastric processing using ID administration of lipid solution formulations decreased drug bioavailability regardless of lipid type. Overall, bioavailability from LCT formulations was higher than MCT regardless of route of administration, consistent with past data after p.o. administration and previously reported descriptions of increases in drug precipitation after administration of medium-chain lipid formulations. The larger differences between bioavailability after both p.o. and ID administration for MCT compared with LCT formulations suggest that passage through the stomach is more critical for MCT formulations, and that gastric digestion may be more critical for MCT than LCT formulations. For MCT-based formulations, efficient dispersion and partial digestion in the stomach may be required to allow rapid transfer to intestinal-mixed micelles and absorption in the upper small intestine prior to drug precipitation.