Multiple injections of subdiabetogenic doses of streptozotocin (SZ) to CD-1 male mice produce a diabetic syndrome that includes a cell-mediated immune reaction against the pancreatic islet. The importance of the host genetic background in the pathogenesis of this model of diabetes was studied by comparing various inbred strains of mice. Of eight strains of mice studied, only C57BL/KsJ developed insulitis and hyperglycemia comparable to that observed in CD-1 mice. In two mouse strains (DBA/J and BALB/cJ) having an H-2d haplotype similar to the C57BL/KsJ, only mild insulitis and glucose intolerance were observed. These data suggest that major histocompatibility complex genes, as presently defined, cannot be the only determinant of the severity of hyperglycemia and insulitis in this model.