OBJECTIVE Insulin resistance is a suspected causative factor in a wide variety of diseases. We aimed to determine whether insulin resistance, estimated by the homeostasis model assessment for insulin resistance (HOMA-IR), is associated with all-cause or disease-specific mortality among nondiabetic persons in the U.S.

RESEARCH DESIGN AND METHODS We determined the association between HOMA-IR and death certificate–based mortality among 5,511 nondiabetic, adult participants of the third U.S. National Health and Nutrition Examination Survey (1988–1994) during up to 12 years of follow-up, after adjustment for potential confounders (age, sex, BMI, waist-to-hip ratio, alcohol consumption, race/ethnicity, educational attainment, smoking status, physical activity, C-reactive protein, systolic and diastolic blood pressure, plasma total and HDL cholesterol, and triglycerides).

RESULTS HOMA-IR was significantly associated with all-cause mortality (adjusted hazard ratio 1.16 [95% CI 1.01–1.3], comparing successive quartiles of HOMA-IR in a linear model and 1.64 [1.1–2.5], comparing the top [HOMA-IR >2.8] to the bottom [HOMA-IR ≤1.4] quartile). HOMA-IR was significantly associated with all-cause mortality only in subjects with BMI <25.2 kg/m² (the median value) but not in subjects with BMI ≥25.2 kg/m². Subjects in the second, third, and fourth quartile of HOMA-IR appeared to have higher cardiovascular mortality than subjects in the lowest quartile of HOMA-IR. HOMA-IR was not associated with cancer-related mortality.

CONCLUSIONS HOMA-IR is associated with all-cause mortality in the nondiabetic U.S. population but only among persons with normal BMI. HOMA-IR is a readily available measure that can be used in the future to predict mortality in clinical or epidemiological settings.