The addition of exogenous superoxide dismutase (SOD) was examined as a possible means of protecting B-cells of mice against either the immediate or delayed toxicity caused by multiple injections of low doses of streptozotocin (Sz). Three different routes of SOD administration (i.p. and i.v. injection and continuous s.c. infusion) and several different doses and schedules were tried. In addition, a long-acting derivative of SOD was synthesized and tested. Despite the observation of a modest delay in the onset of diabetes in one experiment, no protective effect of SOD on the progressive elevation of blood glucose concentrations was evident in the majority of studies. Moreover, a loss in pancreatic insulin content and a tripling of pancreatic glucagon content occurred in all mice treated with low dosages of Sz, irrespective of whether or not either SOD or a long-acting derivative of SOD was administered. Finally, in parallel experiments in vitro, this enzyme was ineffective in protecting isolated rat islets from the acute toxicity of exposure to Sz on glucose-stimulated insulin release.