Human serum, or serum proteins excluded by Sephadex G-25, irreversibly inhibited the ability of mouse pancreatic islet cells to accumulate Rb+. The same treatment reduced the capacity of serum to subsequently inhibit Rb+ uptake by fresh islet cells or to lyse sensibilized sheep erythrocytes. Serum-treated islet cells exhibited electron microscopic signs of damage, including ruptures of the plasma membrane, swelling of mitochondria, and reduced electron density of the cytoplasmic ground substance. Serum induced a prompt insulin release, which was not inhibited by epinephrine. The serum effects were prevented by mild heating (50°C or 56°C, 30 min) but not by treating serum with 10 mM EGTA and 10 mM MgCl2, or with soybean trypsin inhibitor. Inhibition of Rb+ accumulation in response to human serum was also observed with dispersed mouse exocrine pancreas, liver, and spleen cells but not with whole islets. Homologous mouse serum had no effect on mouse liver or spleen cells but significantly decreased the Rb+ uptake by mouse islet cells. Autologous serum had no noticeable effect. It is suggested that mouse islet cells can activate complement via the alternative pathway and that triggering of this pathway is controlled by cellular discriminators of species, organ, and self.