The organophosphate cholinesterase inhibitor soman produced a dramatic increase in arterial blood pressure of up to 60 mm Hg in the unanesthetized rat with variable changes in heart rate. Pretreatment with clonidine resulted in a dose-related inhibition of soman-induced cardiovascular changes and enhanced the time of survival as well as the number of animals surviving 24 hr after soman injection. High doses of clonidine itself produced a transient pressor response; however, the peripheral actions of clonidine were not important for its protective actions. The paradigm of repeated injections of a sublethal dose of soman at regular intervals produced the most reliable cardiovascular changes and degree of lethality. The development of the pressor response under these conditions paralleled the increase in regional brain acetylcholine levels. Pretreatment with a protective dose of clonidine did not alter steady-state levels of acetylcholine, but did inhibit the soman-induced increase in cerebral cortex, medulla-pons, and midbrain, but not that in the striatum. These results are consistent with the ability of clonidine to offer protection against centrally acting acetylcholinesterase inhibitors as a result of marked inhibition of cholinergic function in certain brain regions.