Previous studies have shown that the increased risk of cardiovascular disease in adults with diabetes is independent of heart disease risk factors and have suggested that the effect of these risk factors is similar in diabetics compared with nondiabetics. To determine whether there was interaction between diabetes and the classic heart disease risk factors (cholesterol, blood pressure, and cigarette smoking) in the prediction of cardiovascular death, the etiologic fraction due to interaction was assessed in a nine-year follow-up of 2,620 older Caucasian adults (60-79 years) who resided in Rancho Bernardo, California, 8.7% of whom had diabetes by history of fasting hyperglycemia. In these older adults, the frequency of categoric hypertension, hypercholesterolemia, or current cigarette smoking did not differ significantly among diabetics compared with nondiabetics. Overall, the age-adjusted relative cardiovascular mortality risk among diabetics was similar to that in nondiabetics for all risk factors except cigarette smoking, for which the relative risk for diabetics was 2.2 compared with 1.2 for nondiabetics. High cholesterol and systolic blood pressure levels showed no interaction with diabetes, but cigarette smoking had a large and significant interaction with diabetes, such that an estimated 65% of the cardiovascular disease deaths among diabetics could be attributed to the interaction of diabetes and cigarette smoking. If confirmed, these data have important implications for the prevention of cardiovascular death in older diabetics.