OBJECTIVE: Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers. RESEARCH DESIGN AND METHODS: The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged <25 years, with at least one islet antibody in addition to ICA >or=20 Juvenile Diabetes Foundation units. Median length of follow-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox regression analysis RESULTS: The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0-62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3). CONCLUSIONS: These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.