Nisin is an antimicrobial peptide used as food preservative. To gain some insights into the hypothesis that its bactericidal activity is due to the perturbation of the lipid fraction of the bacterial plasmic membrane, we have investigated the effect of nisin on model phosphatidylcholine (PC) membranes. We show that nisin affects the PC membrane permeability, and this perturbation is modulated by the lipid composition. Nisin-induced leakage from PC vesicles is inhibited by the presence of cholesterol. This inhibition is associated with the formation of a liquid ordered phase in the presence of cholesterol, which most likely reduces nisin affinity for the membrane. Conversely, phosphatidylglycerol (PG), an anionic lipid, promotes nisin-induced leakage, and this promotion is associated with an increased affinity of the peptide for the bilayer because nisin is a cationic peptide. When the electrostatic interactions are encouraged by the presence of 70 mol% PG in PC, the inhibitory effect of cholesterol is not observed anymore. Nisin drastically modifies the morphology of the dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) multilamellar dispersion without causing a significant change in the gel-to-liquid crystalline phase transition of the lipid. The morphological changes are observed from (31)P and (2)H NMR and cryo-electron microscopy. From the NMR point of view, the interactions giving rise to a broad signal (quadrupolar interactions and chemical shift anisotropy for (2)H NMR and (31)P NMR, respectively) are partly averaged out in the presence of nisin. This phenomenon is interpreted by the formation of curved lipid planes that lead to the lipid lateral diffusion occurring in the intermediate motional regime. By cryo-electron microscopy, large amorphous aggregates containing small dense globular particles are observed for samples quenched from 25 and 50 degrees C. Long thread-like structures are also observed in the fluid phase. A structural description of DPPC/nisin complex, consistent with the experimental observation, is proposed. The presence of 30 mol% cholesterol in DPPC completely inhibits the morphological changes induced by nisin. Therefore, it is concluded that nisin can significantly perturb PC bilayers from both the permeability and the structural points of view, and these perturbations are modulated by the lipidic species in the bilayer.