Rats with electrolytic lesions of the ventromedial hypothalamus (VMX rats) and sham-operated controls (SHAM rats) were injected with streptozotocin (STZ) at a dose of 50 mg/kg 48 h after the lesions were made. VMX rats were significantly more sensitive to STZ in that over 70% died within 6 wk, whereas none of the SHAM rats died. When smaller doses of STZ were given to VMX rats (30–35 mg/kg), a large percentage still died, although the survivors appeared equally as diabetic (in terms of hyperglycemia and hypoinsulinemia) as SHAM rats given a larger dose of STZ. At 25 mg/kg, the surviving VMX rats were more hyperglycemic than matched controls. We suggest that the increased B-cell activity known to occur in VMX animals might be the important factor in the increased sensitivity to STZ observed. We speculate that similar variation in pancreatic B-cell response to an environmental injury may be an important determinant of diabetes susceptibility in man.