The development of insulitis in animal models of immune-mediated diabetes mellitus is preceded by an influx of macrophages into the islets. In this study, ICR mice were given four 30-mg/kg doses of streptozocin over 36 h to induce insulitis. The islets were subsequently isolated and cultured in suspension. A macrophage-specific islet infiltration was observed within 48 h of the first drug injection. Concurrent with this leukocyte influx, enhanced in vitro release of a macrophage-specific chemotactic lipid by islets from streptozotocin-administered animals was observed. By chromatographic analysis, the islet-derived chemotactic factor appears to resemble a moderately polar complex lipid that is distinct from previously characterized lipid chemoattractants. Secretion of the factor is not dependent on cyclooxygenase activity. Identification of this lipid may provide important insights into the etiology of insulin-dependent diabetes mellitus and other autoimmune diseases.