The effect of the interleukin-1 receptor antagonist (IL-1ra) on development of hyperglycemia and insulitis in mice treated with multiple low doses of streptozotocin (STZ) was evaluated. C57BL/Ks mice were subjected to the following treatments: 1) Injections i.p. of phosphate-buffered saline (PBS) alone; 2) STZ (5 x 40 mg/kg bw); 3) STZ + PBS delivered by an osmotic pump implanted s.c; 4) STZ + IL-1ra delivered by an osmotic pump (approximately 8 mg/kg bw) for 12-14 days starting on day 5, the last day of STZ injection. IL-1ra had a clear protective action against hyperglycemia and insulitis until day 19, i.e., on cessation of IL-1ra administration. Thus, the results indicate that sustained administration of IL-1ra can prevent the diabetogenic process elicited by low dose STZ treatment, suggesting that IL-1 may have a role in the pathogenesis of this form of diabetes.