The mesencephalic dopaminergic system has been implicated in the motor and cognitive operations of the cerebral cortex as well as in the pathogenesis of neurological and psychiatric disorders. However, to date, the dopamine (DA)-containing axons of the primate cerebral cortex have not been directly visualized immunohistochemically due to the lack of a DA-specific antibody. We have now analyzed the regional and laminar distribution of DA-immunoreactive (DA-IR) afferents in the frontal cortex of the rhesus monkey using a monoclonal antibody specific for DA. In addition, we compared the distribution of DA-IR processes to tyrosine hydroxylase (the rate-limiting enzyme in DA synthesis) immunoreactive (TH-IR) axons. Frontal cortex displays an elaborate and robust dopaminergic innervation. Although regional differences in the DA-IR innervation were clearly evident, variations in the DA innervation were essentially unrelated to cytoarchitectonic boundaries. Instead, the DA innervation followed two basic gradients: (1) a prominent medial-to-lateral gradient of decreasing fiber density that was most prominent in the dorsal cortical regions, and (2) a more subtle anterior-posterior gradient in which DA-IR fiber density decreased slightly in both rostral and caudal directions from a peak density centered in the region of granular frontal area 8Bm and the supplementary motor area 6M. The laminar pattern of DA-IR axons also showed regional variations that again were typified by smooth transitions irrespective of cytoarchitecture. Analysis of DA-IR axonal morphology indicated that immunoreactive fibers form a basically uniform population, giving little evidence of a bimodal heterogeneity evident in other species.(ABSTRACT TRUNCATED AT 250 WORDS)