Systemic (i.p. and p.o.) administration of clonidine significantly reduced the acute inflammatory swelling of the rat paw produced by carrageenin, histamine and serotonin. Clonidine did not reduce carrageenin swelling when given i.c.v. Intraperitoneal administration of a structural analog of clonidine, 2-(2-methyl-4- chlorophenylamine ) -2-imidazoline (CDMI), was only effective against carrageenin swelling. CDMI was 10 times more effective when given centrally (i.c.v.) than when given systemically (i.p. or p.o.). The slopes of the individual dose-response curves were not significantly different which suggested a common mechanism of action. However, although adrenalectomy did not reduce the anti-inflammatory activity of i.p. CDMI, i.c.v. CDMI was ineffective in adrenalectomized rats. These results indicate that imidazolines represent a unique class of anti-inflammatory agents with actions mediated both peripherally and centrally.