To map the unknown distribution of histamine H-3 binding sites, we compared autoradiographs of the binding of the H-3 agonist N-alpha-[H-3]methylhistamine ([H-3]NAMH) in the forebrain of mouse and guinea pig. Saturation binding revealed the presence of a single site with apparent affinity of 0.75 nM in the mouse and 1.2 nM in the guinea pig. Binding constants were nearly identical in male and female mice. The rank order of [H-3]NAMH binding in mouse brain was striatum > insular cortex > neocortex, as previously observed in the rat. In the guinea pig, the rank order was insular cortex > striatum approximate to neocortex. The B-max of [H-3]NAMH in insular cortex of both species was close to 60 fmol/mg. Thus, the guinea pig differs from the rodent in that the highest density of H-3 binding was present in cortical rather than subcortical structures.