We investigated the interaction between manganese(III)mesoporphyrin (MnMeso), a metalloporphyrin, and liposome membranes containing oleic acid (OA; cis-9-octadecenoic acid). MnMeso associates preferentially with OA but minimally with egg phosphatidylcholine (EPC). Using small unilamellar vesicles, we characterized the MnMeso-OA binding at neutral pH. Our data suggest that MnMeso binds to the OA bilayer with Kd = 6.8 x 10(-4) M; the binding stoichiometry of MnMeso-OA was 1:3.4. This OA-MnMeso interaction was analyzed further for changes in the T1 relaxation property of MnMeso. OA increased the T1 of MnMeso significantly more than did EPC, suggesting that the OA-MnMeso interaction was stronger than that of PC-MnMeso. The side-chain specificity of the OA interaction with this porphyrin derivative was further supported in an experiment with manganese mesotetra(4-sulfonatophenyl)porphine, which lacks hydrophobic side chains for OA interaction. The association of MnMeso with the OA membrane was proposed according to the structure of MnMeso and OA and further verified using electron microscopy. A strong association of MnMeso with OA, an absorption enhancer of the gastrointestinal tract, may be useful for delivery of MnMeso as an oral contrast agent for magnetic resonance imaging.