The effect of intravenous infusion of heat-aggregated IgG on vascular permeability was studied by using 51Cr-labelled homologous red blood cells in mice. Simultaneously, the recovery of platelet-activating factor (PAF) from the mononuclear phagocytic system (MPS) was attempted. Whereas PAF was found only in trace amounts in the liver of control animals, the infusion of aggregates induced the release of PAF from liver and spleen in a time- and dose-dependent manner. A possible link between PAF release and permeability is sustained on the following basis. PAF release precedes permeability changes and both show a parallel dose-response pattern plateauing for doses higher than 1 mg. Further, depletion of mononuclear phagocytes by total irradiation with 700 rads, or pharmacological blockade of phospholipases by prior treatment with quinacrine, induced abrogation of permeability changes and PAF release from spleens, together with an 80% reduction of the amount of PAF obtained from livers. These data suggest the following conclusions: 1) PAF release may occur in vivo when the MPS is stimulated by phagocytosable material; 2) PAF seems to be an effector substance of the permeability changes which occur during the administration of immune aggregates.