The arrangement of the various endocrine cells within mammalian islets of Langerhans indicates that the regulation of insulin and glucagon secretion by pancreatic somatostatin may occur mainly by paracrine mechanisms. In the present study, the relationship of somatostatin-containing D-cells to blood vessels and to other endocrine cells in the islets of the human pancreas were investigated using immunohistochemically stained serial semithin sections (0.5-1.0 micron). Morphologic features of 335 D-cells were examined and their anatomical relationship to other endocrine cell types and capillaries was determined by morphometric analysis and graphic or three-dimensional reconstructions. The majority of D-cells (84%) was located in close proximity to the capillaries. The intracellular immunoreactive material was accumulated in those cell parts facing the capillaries or their perivascular spaces. The remaining D-cells did not come into contact with the capillaries and showed only moderate or weak immunoreactivity.--A further characteristic feature of islet D-cells, pertinent to about 67% of these cells, is their tendency to be arranged in contiguity to other D-cells. The present findings indicate that somatostatin after its release from the D-cell reaches other islet cells mainly via the intrainsular circulation or along the perivascular space. Concerning the general microarchitecture of human islets of Langerhans, the present data are not sufficient to give a conclusive morphological description, because heterogeneities among the islets were observed. These variations appear to be related to the type of vascular supply which differs among islets.