The properties of a novel platelet-activating factor (PAF) antagonist, L-652731, on oedema responses in rabbit skin induced by exogenous inflammatory mediators and by mediators generated endogenously in a reversed passive Arthus reaction have been investigated. Oedema responses in the skin were measured by using the local accumulation of i.v. injected 125I-albumin. The antagonist, mixed with mediators before intradermal injection, caused a dose-dependent suppression of oedema responses to PAF. In contrast, responses induced by other directly acting mediators (bradykinin and histamine) and responses induced by PMN leukocyte-dependent mediators (C5a des Arg, N-formyl-methionyl-leucyl-phenylalanine, and leukotriene B4) were not suppressed. Thus, a secondary release of PAF does not appear to be involved in mediating the actions of these agents. In a reversed passive Arthus reaction, intradermal injection of L-652731 together with antibody resulted in a significant inhibition of the oedema formation measured for 2 hr after i.v. antigen challenge. In contrast, oedema responses induced by intradermal injection of preformed immune complexes were not affected by the antagonist. These results suggest that the endogenous production of PAF, in close proximity to microvascular endothelial cells, appears to be an important step in the development of an Arthus reaction. The cellular source of PAF is unknown, but one possibility is the PMN leukocyte, which releases PAF during phagocytosis of immune complexes.