To confirm the immunological basis of type I diabetes and to determine if immune intervention alters the course of the disease, we studied the use of cyclosporine in a 1-year randomized, double-masked, placebo-controlled trial in 23 subjects enrolled within 6 weeks of diagnosis. Subjects included 12 males and 11 females, ages 9-38 years (mean, 19.7 +/- 1.8 years). Initial dosage of cyclosporine was 10 mg/kg/day, given as a single daily dose, adjusted on the basis of side effects and trough cyclosporine levels. Glycemic control and insulin dosage were similar in both cyclosporine and placebo groups. The frequency of freedom from insulin usage also was similar in both groups; however, it is not possible to draw conclusions about response rates, because of the very small sample size. Glucose tolerance, as measured by rate of intravenous glucose disposal did not differ between groups. Islet beta cell function was measured by determining C-peptide response to three secretogogues: intravenous glucagon, intravenous glucose, and a mixed formula meal (Sustacal). There were no differences between groups in the C-peptide responses either to intravenous glucagon or intravenous glucose. Moreover, acute insulin response to intravenous glucose was not restored in any subject. On the other hand, in comparison to the placebo group, the cyclosporine group did show an increased meal-stimulated C-peptide response after 3, 6, 9, and 12 months. When measured by regression analysis, the slope defining the rate of decline of beta cell function was significantly slower for the cyclosporine group than the placebo group (p less than 0.05). Thus, as measured in response to a physiological stimulus (meal challenge), cyclosporine preserves islet beta cell function when used in recent onset type I diabetes. Side effects were minimal and reversible upon cessation of immune intervention. The preservation of islet beta cell function by immune intervention is consistent with the hypothesis that type I diabetes has an immune mechanism involved in its pathogenesis.