Morphology and structural organization of calcitonin gene-related peptide (CGRP) immunoreactive nerve fibers and islet cells in rat pancreas were analyzed with light and electron microscopic immunocytochemistry. Immunoreactive axons innervate exocrine and endocrine parenchyma, but are most abundant in connective tissue septae between pancreatic lobules and within the perivascular space of small arterioles. In the stromal compartment and perivascular space, immunoreactive product is confined to thin, unmyelinated axons, which represent a prominent component of large nerve bundles, composed of numerous, other, unlabeled axons and dendrites. Immunoreactive axons and terminals display multiple varicosities, filled with lucent spherical vesicles (40 nm average diameter), and are often in direct contact with unlabeled dendrites, presumed to arise from intrinsic pancreatic neurons. However, definitive synaptic contacts involving immunoreactive axon terminals were never observed, nor was CGRP immunoreactivity ever detected in neuronal cell bodies within intrapancreatic ganglia. Cellular immunoreactivity is relegated to perikarya at the peripheral margin of each islet of Langerhans, which emit one or more short, thick processes, which often terminate upon fenestrated capillaries. Immunoreaction product in these cells is concentrated in large secretory vesicles (approximately 230 nm diameter), which are dispersed throughout the somata and frequently appear to open into the perivascular space of capillaries. Immunoreactive axons, innervating the islets, are sparse and do not appear to have preferential association with immunoreactive cells. Present findings provide further evidence for a dual role of CGRP in pancreatic functions via a neuronal pathway and hormonal mechanisms.