It has recently been reported that high molecular weight microtubule-associated proteins are differently distributed in dendrites and axons of neurons [ Matus Bernhardt and Hugh-Jones (1981), Proc. natn Acad. Sci. U.S.A. 78, 3010-3014; Vallee (1982), J. Cell Biol. 92, 435-442]. We have reported earlier in a preliminary form [Miller, Walter, Theurkauf , Vallee and De Camilli (1982), Proc. natn Acad. Sci. U.S.A. 79, 5562-5566] that an antiserum specific for microtubule-associated protein 2, one of the most prominent high molecular weight microtubule-associated proteins in brain and a major brain phosphoprotein, stains specifically neuronal dendrites and perikarya. We have now extended those observations by performing a detailed analysis of the distribution of microtubule-associated protein 2 throughout the nervous system of the rat. We found that microtubule-associated protein 2 is present at high concentrations in the great majority of neurons. Under our conditions of immunostaining microtubule-associated protein 2 was not detected in nonneuronal cells. In all neurons it was compartmentalized in perikarya and dendrites. In most cases, the latter were more heavily stained than perikarya. The pattern of staining (overall intensity, relative intensity in dendrites vs perikarya, and in proximal vs distal segments of the dendritic tree), varied in different classes of neurons but was identical for all neurons with similar geometry in the same brain region. Different patterns of staining were found in dendritic trees with dissimilar branching characteristics. In all cases staining for microtubule-associated protein 2 in dendrites was consistent with a localization of microtubule-associated protein 2 on dendritic microtubules. Neuronal processes clearly identifiable as axons or axon terminals were not immunostained. Afferent processes of primary sensory cells were also unstained. Our findings indicate that microtubule-associated protein 2 is a component of the vast majority, and possibly all, neurons. It is highly concentrated in "bona fide" dendrites, i.e. in processes specialized for the reception of synaptic inputs on their surface and highly dependent on such inputs for their growth. The location of microtubule-associated protein 2, a major target for second messenger-regulated protein kinases, in these processes, supports the hypothesis that its phosphorylation might participate in the transduction of neurotransmitter signals in target nerve cells.