Halofantrine hydrochloride is an important, highly lipophilic anti-malarial agent. A triple-cannulated anesthetized rat model was used to investigate the potential lymphatic transport of halofantrine (Hf). The effect of formulating Hf in vehicles representative of different physical (digestion) states of triglyceride lipid was also evaluated. The lipid vehicles were either a lipid solution, emulsion, or micellar system comprised of 50 microL of a 2:1 molar ratio of oleic acid:glycerol monooleate containing 2 mg of Hf free base. Lymph was collected from the mesenteric lymph duct, and blood was sampled from the jugular vein following intraduodenal infusion of the different formulations. Lymphatic transport was a major contributor to bioavailability as demonstrated by the recovery of up to approximately 20% of the administered dose in the intestinal lymph. The rank order effect of the vehicles for the promotion of lymphatic transport was micellar > emulsion > lipid solution. Lymphatic drug transport was predominantly associated with chylomicron-based transport. The extent of Hf absorption via the portal blood, estimated from the systemic plasma profiles in the lymph-cannulated rats, was largely independent of the administered formulations. These data indicate that lymphatic transport of the free base of Hf is a major contributor to oral bioavailability when formulated in appropriate lipid vehicles. The data suggest that formulation as increasingly disperse systems facilitates transport in this animal model.