Type i (insulin-dependent) diabetes mellitus results from autoimmune cell-mediated destruction of pancreatic islet Beta cells. Since theophylline has suppressive effects on immune responses, we sought to determine if this agent might protect against destruction of islet Beta cells in diabetes-prone BB rats. Diabetes-prone rats were divided into four groups and treated, from age 30 to 125 days, with: (a) no treatment (control), (b) theophylline 2 mg. ml-1 added to the drinking water, (c) cyclosporine 5 mg. kg -1. day -1 administered by gavage, and (d) theophylline plus cyclosporine. By age 125 days, diabetes (glucosuria and serum glucose > 11 mmol.l 1) had appeared in 15 of 17 (88%) of control rats, 10 of 18 (56%) on theophylline, 6 of 17 (35%) on cyclosporine, and 1 of 17 (6%) on theophylline plus cyclosporine. Protection against diabetes by theophylline and cyclosporine was associated with preservation of pancreatic Beta cell mass (insulin content). The protective effects of combination therapy with theophylline and cyclosporine were achieved at very low serum concentrations of cyclosporine. These findings suggest that theophylline may be a useful adjunct in the immunosuppressive therapy of Type 1 diabetes.