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To determine the predictors of lower extremity amputation (LEA) in a cohort of persons with diabetes (primarily non-insulin-dependent).We conducted a nested case-control study among 10,068 patients from a large health maintenance organization who reported a diagnosis of diabetes at a multiphasic health checkup (MHC) (baseline) between 1964 and 1984. Average length of follow-up after baseline was 13.2 years. Case patients were 150 cohort members with a first, nontraumatic LEA after baseline. Control subjects were 278 cohort members who did not experience an LEA during follow-up, matched to patients on age, sex, and year of baseline MHC. The presence of diabetes at baseline was verified by chart review for both patients and control subjects. Cardiovascular disease risk factors were obtained at the baseline MHC; glucose control, other diabetes-related variables, preventive services, and other complications were obtained from chart review.Level of glucose control (P < 0.0001), duration of diabetes (P = 0.04), and baseline systolic blood pressure (P = 0.004) were independent predictors of amputation, as were microvascular complications (retinopathy, neuropathy, and nephropathy). History of stroke, but not myocardial infarction, was also independently predictive; type of diabetes, cigarette smoking, and total cholesterol level were not. Being African-American was unrelated to amputation risk in univariate or multivariate analyses in this insured population.LEA shares a risk factor profile with other microvascular complication of diabetes. Thus, control of blood glucose and blood pressure should reduce risk for amputation. African-Americans do not appear to be at increased risk for diabetes-related amputation when access to medical care is comparable.