The cytologic composition of the pancreatic islets of 58 insulin-dependent diabetics with age of onset of the disease before the age of 40 and a duration of from a few days to 37 years was studied with the aid of Sternberger's immunocytochemical method. Four types of islet cells were stained with specific antisera: β cells (insulin), α cells (glucagon), D cells (somatostatin), and PP cells (pancreatic polypeptide). β cells were found in 14 of 16 recent-onset cases, in seven of 14 patients having diabetes for less than 11 years, and in five of 28 patients in whom the disease had been present for a longer time. In all these cases, the number of β cells was well below normal. They showed cytologic features of functional hyperactivity. The majority of the islets, even in recent-onset cases, were devoid of β cells and were composed of thin cords of islet cells. Immunocytochemical staining revealed that, contrary to the classic opinion, these cells are not inactive but are actively secreting glucagon or somatostatin. In many long-term juvenile diabetics, the glucagon-containing α cells appeared very numerous, but it remains to be ascertained whether this represents an apparant or a true hyperplasia. Insulitis was found in 11 of the 16 recent-onset cases. In one case, the lymphocytic infiltration was found only in islets containing β cells but was strikingly absent in the islets composed of glucagon-, somatostatin-, and PP-cells. Images of islet regeneration, with neoformation of β cells and other islet-cell types from centroacinar and ductular cells could still be detected focally in a few recent-onset cases. With a disease of longer duration, an atypical type of islet regeneration, originating in the epithelium of small- and medium-sized ducts, becomes more prevalent and produces islets solely composed of PP cells.