The distribution of the prosomatostatin-derived peptides (PSDP) somatostatin-28 (SS-28) and somatostatin-281-12 (SS-281-12) was characterized immunohistochemically in the prefrontal cortical regions of both Old World cynomolgus monkeys (Macaca fascicularis) and New World squirrel monkeys (Saimiri sciureus). Comparison of staining with antisera specific for each peptide revealed that these antigens were segregated within immunoreactive neurons such that SS-28 was largely confined to the perinuclear region of the cell body whereas SS-281-12 was primarily found in axons and dendrites. The laminar pattern of immunoreactive fibers was similar in all areas of the prefrontal cortex. The most dense terminal arborization was in layers I, II, and superficial III. Deep III and IV were traversed by radial fibers that had little arborization. Layers V and VI contained both radial fibers and a moderately dense terminal plexus. Labeled fibers were less numerous in the white matter. There were marked regional differences in fiber density. Areas 12 and 24 had the greatest density of immunoreactive fibers, areas 9, 11, and 25 were of intermediate density, and areas 10 and 46 were the least dense. Most of the immunoreactive cells appeared to be multipolar or bitufted. They were found throughout all cortical layers and the white matter. The largest number were located in layers II, superficial III, and deep V and VI. There were also marked regional differences in cell body density, which paralleled the regional differences in fiber density. Area 24 (anterior cingulate) had the greatest density of immunoreactive cell bodies (148 +/- 14/mm2), area 9 was of intermediate density (109 +/- 13/mm2), and area 46 was the least dense (83 +/- 12/mm2). Our findings indicate that PSDP compose a complex and extensive cortical system that is largely or totally intrinsic. The substantial regional heterogeneity in density exhibited by PSDP-containing neurons has not previously been reported for an intrinsic cortical system. The laminar and regional innervation patterns of these fibers and cell bodies suggest that the PSDP cortical system may play an important role in the polymodal information processing that occurs in association regions of prefrontal cortex.