To address the question of whether elevated concentrations of nonesterified fatty acids (NEFAs) are associated with an increased risk of cardiovascular disease, we measured NEFA concentrations in 140 diabetic and 343 nondiabetic unrelated Swedish subjects with a family history of type 2 diabetes and related the findings to history of cardiovascular disease in their parents. Parents of nondiabetic offspring belonging to the quartile of highest NEFA concentrations had a higher risk of myocardial infarction (35% versus 16%, P<0.01) and stroke (45% versus 16%, P<0.0005) than did parents of offspring from the lowest NEFA quartile. In a multiple logistic regression analysis, a high NEFA concentration in offspring was significantly associated with myocardial infarction and stroke in their parents. No such relationship was observed between diabetic offspring and their parents. Assuming that the same relationship between NEFA concentrations and cardiovascular disease is seen in the offspring and their parents, the findings suggest that elevated NEFA concentration is a risk factor for cardiovascular disease and could be pathogenically involved in the atherosclerotic process.