The binding of [3H]rilmenidine to membranes of rat cerebral cortex was studied in order to ascertain which receptor populations this novel antihypertensive interacts with in the cortex. A catecholamine-sensitive, alpha 2-adrenoceptor binding site was identified which represented up to 50% of specific, 2 nmol/L [3H]rilmenidine binding and was displaceable by the catecholamines in the rank order epinephrine----norepinephrine----dopamine----isoproterenol. Some imidazolines such as clonidine, naphazoline, and idazoxan and the guanidino compound guanabenz completely and potently inhibited [3H]rilmenidine binding from both catecholamine-sensitive and -insensitive sites. The substituted imidazole and guanidine, cimetidine, and amiloride, respectively, showed no affinity for [3H]rilmenidine binding. The pharmacologic profile of the catecholamine-insensitive [3H]rilmenidine site in rat cerebral cortex suggests it may be novel, as it has the features of an imidazoline-guanidino-oxazoline binding site. However, its identity requires further characterization.