Many studies have examined the role of age, islet cell antibodies (ICAs), insulin autoantibodies (IAAs), and first-phase insulin responses (FPIRs) to an intravenous glucose tolerance test (IVGTT) as markers of risk of progression to IDDM, but a large data set is required for the analysis of the interactions between these markers. The Islet Cell Antibody Register Users Study (ICARUS) register includes 456 first-degree relatives with ICA levels > or = 5 JDF U confirmed in a reference laboratory, 108 of whom have progressed to IDDM in the course of prospective follow-up. Analysis of this data set confirmed the importance of the loss of FPIR, high ICA titer, coexistence of IAA, and young age in enhancing the risk of progression to the disease. The influence of any given marker of risk is modified by the presence or absence of the other markers. Cox regression analysis performed in a subset of 217 subjects for whom IVGTT, ICA, and IAA data were available showed that risk was most strongly associated with loss of FPIR; IAA and ICA titer contributed equally to the model, while age was also an independent risk determinant.