Lysis of rat islet cells by syngeneic activated macrophages in vitro can be completely inhibited by the nitric oxide-synthase-inhibitor N^G-methyl-l-arginine. This inhibition can be reversed by an excess of l-arginine. Time-dependent lysis of islet cells by activated macrophages is accompanied by increasing concentrations of nitrite and citrulline in the culture medium both of which are measures of nitric oxide formation derived from l-arginine. Lysis of isolated islet cells and disintegration of isolated whole islets is also obtained within 15 h by culture in the presence of the nitric oxide generating vasodilator sodium nitroprusside. We thus conclude that nitric oxide is extremely toxic for islet cells and that nitric oxide alone and in the absence of other macrophage-generated potentially toxic products can rapidly and completely kill islet cells.