An H3-agonist, R alpha methylhistamine strongly relaxed isolated and perfused rabbit middle cerebral artery precontracted with K+. This vasodilatation was not antagonized by either mepyramine or cimetidine but was competitively antagonized by an H3-antagonist, a mixture of impromidine and cimetidine. Histamine activated the H3-sites in this artery since its concentration-response curve (obtained with mepyramine and cimetidine) was parallel to that of R alpha methylhistamine. Our data indicate that H3-sites could exist in the rabbit cerebral artery.