OBJECTIVE: The purpose of this study was to determine whether insulin resistance is a risk factor for the development of type 1 diabetes in autoantibody-positive first-degree relatives of diabetic family members. RESEARCH DESIGN AND METHODS: Subjects (n = 186) who had a projected 25-50% risk for diabetes and subjects (n = 170) who had a projected >50% risk for type 1 diabetes in 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial-Type 1. We assessed insulin secretion with the first-phase insulin response (FPIR) and insulin resistance with homeostasis model assessment of insulin resistance (HOMA-IR) from an intravenous glucose tolerance test. The median follow-up was 4.3 years for moderate-risk subjects and 3.7 years for high-risk subjects. RESULTS: During the follow-up period, 53 subjects in the moderate-risk group and 70 subjects in the high-risk group developed type 1 diabetes. After adjustments for confounders using multivariate analysis, HOMA-IR and the FPIR-to-HOMA-IR ratio were significantly associated with type 1 diabetes in both risk groups. In the moderate-risk population, the hazard ratio (HR) of HOMA-IR was 2.70 (95% CI 1.45-5.06) and the HR of FPIR-to-HOMA-IR was 0.32 (95% CI 0.18-0.57). In the high-risk population, the HR of HOMA-IR was 1.83 (95% CI 1.19-2.82) and the HR of FPIR-to-HOMA-IR was 0.56 (95% CI 0.40-0.78). CONCLUSIONS: There is clear evidence of the association between insulin resistance and progression to type 1 diabetes. The combination of FPIR and HOMA-IR could be used as a better metabolic indicator for type 1 diabetes risk for prediction and suggests possible intervention strategies for diabetes prevention.