Cytoplasmic pancreatic islet cell antibodies were found in 21% of 244 unaffected first degree relatives of type I diabetic patients. Twenty-five percent of HLA-identical, 35% of HLA-haploidentical, 16% of HLA-nonidentical siblings, and 14% of parents were ICA-positive. In the HLA-identical sibs, irrespective of ICA, and in the 18 ICA-positive parents but not the other groups, increased plasma glucose levels were observed after the administration of glucose. In most children, these were associated with reduced insulin levels, while in the adults elevated insulin responses were noted. In 48% of the ICA-positive children and 84% of the ICA-positive parents, other evidence of "autoimmunity" was obtained either by history or by testing for specific autoantibodies. Two of the originally unaffected HLA-identical and ICA-positive siblings developed diabetes during the course of the study. These findings, plus previously reported data in families with two diabetic sibs demonstrating that the empiric risk for developing IDDM is of the order of 30% for HLA-identical sibs but less than 5% for those that are HLA-haploidentical, suggest that HLA-identity may be a useful predictor of potential type I diabetes. The presence of ICA may, at times, portend the need for future antidiabetic therapy but prospective studies must be continued to fully elucidate this relationship.