Using an indirect immunofluorescence test on suspensions of viable, insulin-producing islet cells from rats, we found that 32 per cent (28/88) of insulin-treated patients with juvenile diabetes have isletcell-surface antibodies in their circulation. These antibodies also occurred in four of nine children with glucose intolerance, in one of 24 healthy children and in nondiabetic children with thyroid disorders. In the diabetic children, the immunofluorescent reaction was inhibited by preadsorption of serum to islet cells but was little affected by preadsorption to rat hepatocytes or erythrocytes or to acetone powders of various rat tissues, including pancreas. These results show that organ-specific, non-species-specific antibodies reactive with the cell surface of the islet cells can be present in serum from diabetic children, and provide an approach to investigation of immunopathological aspects of diabetes mellitus. (N Engl J Med 299:375–380, 1978) INSULIN-dependent diabetes mellitus in children and adolescents is characterized by a dramatic decrease in glucose-induced insulin secretion and a progressive loss of endogenous insulin production that is concomitant with a disappearance of beta cells from the pancreatic islets. Although the pathologic process that precipitates insulin-requiring diabetes is not understood, a substantial body of recent work suggests that immune mechanisms may be involved. Specifically, Gepts1 found lymphocytic infiltration of the pancreatic islets in nearly 70 per cent of patients with juvenile-onset diabetes of short duration. Evidence for cell-mediated immunity specific for the endocrine pancreas was obtained in newly diagnosed diabetics by.