The contribution of lymphatic transport and absorption directly into the portal blood to the overall oral bioavailability of a model lipophilic drug, halofantrine (Hf), was determined in lymph‐cannulated, conscious, unrestrained rats after administration in lipidic vehicles with different fatty acid chain lengths. Both lymphatic transport (C18‐based vehicle, 15.8% of dose > C8–10, 5.5% > C4, 2.22% > C0, 0.34%) and total systemic exposure (C18, 22.7% of dose > C8–10, 19.2% > C4, 15.2% > C0, 6.4%) of Hf were enhanced by the presence of lipids in the formulation and specifically by an increase in the fatty acid chain length of the coadministered lipid. Increases in lymphatic drug transport appeared to correlate with increases in lymphatic lipid transport. Surprisingly, where lymphatic transport was the primary mechanism of drug transport to the systemic circulation (i.e., after administration in a C18‐based lipid vehicle), Hf bioavailability assessed in nonlymph‐cannulated animals was lower than the extent of total availability measured in lymph‐cannulated animals (estimated as percent appearing in the intestinal lymph plus percent transported directly into the blood), suggesting either presystemic drug clearance within the lymphatics or an altered systemic clearance pattern for lymphatically transported drug. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1073–1084, 2000