The primate orbitofrontal cortex is a component of the paralimbic cortical "belt" and consists of several distinct areas. It is involved in high order association functions that include the integration of emotion, behavior, and various sensory processes. To define the cyto- and chemo-architectonic organization of the human orbitofrontal cortex, we have used antibodies to the nonphosphorylated neurofilament triplet protein and to the calcium-binding proteins parvalbumin and calretinin. Immunohistochemistry revealed labeling patterns corresponding to the cytoarchitecture defined by Nissl preparations. Neurofilament protein-immunoreactive pyramidal neurons were located only in layers V-VI in the agranular posterior orbitofrontal cortex, whereas they were distributed in both layers III and V-VI in the anteromedial and anterolateral granular regions. The intermediate dysgranular portion of the orbitofrontal cortex represented a transition zone with a progressive decrease in layer III labeled pyramidal cell numbers posteriorly. The distribution of parvalbumin- and calretinin-immunoreactive interneurons was more homogeneous, although the posteromedial region and the cortex of the inferior rostral sulcus had slightly lower parvalbumin-positive neuron counts than the other orbitofrontal areas. Parvalbumin immunoreactivity in the neuropil exhibited a high degree of regional specialization in that it was consistently less intense in the cortex of the intermediate and posterior part of the gyrus rectus, whereas the other orbitofrontal areas had a very dense neuropil staining in layers III to V. Also, there was a dense plexus of parvalbumin-immunoreactive fibers restricted to layer I in the posterolateral orbitofrontal cortex, and patches of neuropil staining in layer III of the inferior rostral sulcus. These region-specific neuropil staining patterns may correspond to the distribution of parvalbumin-immunoreactive thalamocortical projections to distinct domains of the orbitofrontal cortex. This regional parcellation of the human orbitofrontal cortex as defined by specific neuronal markers, may represent an anatomical substrate for the localization of the various functions attributed to this poorly understood cortical region.