Action of several solutes on the kinetics of phospholipase-A2-catalyzed hydrolysis of the ternary codispersions containing dimyristoylphosphatidylcholine + 1-palmitoyllysophosphatidylcholine + palmitic acid is examined. The kinetics of hydrolysis is interpreted in terms of the ability of the enzyme to bind to the substrate interface. The inhibitory effect of these solutes is correlated with their ability to modify fluorescence intensity of the bound enzyme, to modify the phase-transition profile, and to inhibit aggregation/fusion of the ternary codispersions. Based on these observations, it is suggested that the solutes like n-alkanols, ketamine, alphadolone, alphaxalone, flufenamic acid, tobramycin, mepacrine, EMD 21657 and U-10029A modulate the phase equilibria in the codispersions and thus noncompetitively inhibit the phospholipase action. Inhibition by feverfew extract (Tanacetum parthemium) is also by a similar mechanism. Lipid-soluble drugs as indomethacin had little effect on the kinetics of hydrolysis. All these inhibitors decrease the total extent of hydrolysis of the available substrate. However, none of these inhibitors have any effect on the hydrolysis of monomeric substrate or on the inactivation of the phospholipase A2 by p-bromophenacylbromide. These observations suggest that all these inhibitors do not interact directly with the catalytic site of the free or the bound enzyme, and their effect is primarily on the enzyme-binding sites on the substrate vesicle, that is, by perturbation of lipid-protein interaction.