The proinflammatory cytokine, interleukin (IL)-1beta, is known to induce vascular dysfunction and cell death. We investigated the role of IL-1beta and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Caspase-1 activity is increased in retinas of diabetic and galactosemic mice and diabetic patients. First, we investigated the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1beta production and retinal capillary degeneration in diabetic and galactose-fed mice. Second, we examined the effect of genetic deletion of the IL-1beta receptor on diabetes-induced caspase activities and retinal capillary degeneration. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5 mg/kg). At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1beta production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro but not in vivo. Mice deficient in the IL-1beta receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. These results indicate that the caspase-1/IL-1beta signaling pathway plays an important role in diabetes-induced retinal pathology, and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy.