1,25 dihydroxyvitamin D3, the active form of vitamin D, has immunomodulatory properties in vitro and in vivo. We report that treatment with 1,25 dihydroxyvitamin 03 (5 gg/kg on alternate days) prevents the development of clinical diabetes in NOD mice, an animal model of human autoimmune diabetes. Diabetes incidence in female NOD mice at the age of 200 days was reduced to 8 % in the 1,25 dihydroxyvitamin D treated group vs 56% in the control group (p < 0.0001). In parallel, treatment with 1,25 dihydroxyvitamin D 3 resulted in a complete normalisation of the capacity to induce suppressor mechanisms in an autologous MLR, which is severely depressed in control NOD mice. The existence of such suppressor ceils was confirmed in transfer experiments, whereby cotransfer of splenocytes from 1,25 dihydroxyvitamin D3 treated NOD mice prevented diabetes transfer by splenocytes from diabetic NOD mice into irradiated, 6-8-week-old male NOD mice. Other known immune defects of the NOD mice, such as defective natural killer cell killing of YAC-1 targets and defective thymocyte activation by anti-CD3 were not corrected. The pharmacological doses of 1,25 dihydroxyvitamin D3 were universally well tolerated as reflected by a normal weight gain of the mice. Serum calcium was increased (2.5+0.2 vs 2.2 + 0.2 mmol/1 in the control group,p < 0.005), whereas osteocalcin levels nearly doubled and bone calcium content was halved. These findings show that 1,25 dihydroxyvitamin D3 can prevent diabetes in NOD mice, probably through the correction of their defective suppressor function. [Diabetologia (1994) 37: 552-558] Key words Autoimmunity, immunotherapy, suppressor cells, insulitis, vitamin D analogues The NOD mouse is an animal model for human autoimmune diabetes (IDDM or juvenile diabetes), characterized by destruction of the insulin producing beta cells of the islets of Langerhans in the pancreas. The precise immune mechanisms leading to this destruction remain unclear [1-3]. Defective elimination of autoreactive T-cell clones or impaired suppressor mechanisms are the most acceptable hypotheses [4]. Conse-