Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type 1 diabetic patients. Relatives were prospectively followed for 2 304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas others remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common. Despite current knowledge and available genetic and immune markers, early identification of the relatives progressing to clinical diabetes is still difficult and does not allow at the present time aggressive immunointervention at the prediabetic stage.