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To determine the association between triglyceride levels and lower-extremity amputation (LEA) risk in a large diabetic cohort.This is a 10-year survey follow-up study (from 1995–2006) of 28,701 diabetic patients with a baseline triglyceride measure. All patients were fully insured members of the Kaiser Permanente Medical Care Program and responded to a survey at baseline that included information on ethnicity, socioeconomic status, education, behavioral factors, and information required to determine type of diabetes. The relationship between triglycerides and time to incident nontraumatic LEA, defined by primary hospitalization discharge or procedures, was evaluated using Cox proportional hazards models.Triglyceride level was an independent, stepwise risk factor for nontraumatic LEAs within this large diabetic cohort: triglycerides 150–199 mg/dL, hazard ratio (HR) 1.10 (95% CI 0.92–1.32); 200–499 mg/dL, 1.27 (1.10–1.47); >500 mg/dL, 1.65 (1.30–2.10) (reference <150 mg/dL).Hypertriglyceridemia is a significant risk factor for LEA in diabetic patients even after controlling for known socioeconomic, health behavioral, and clinical factors. This previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk.