The influence of fibrinogen on the risk of cardiovascular disease is examined over 16 years of follow-up in 1314 subjects who were initially free of cardiovascular disease in the Framingham Study. Of these subjects, 46 men and 43 women developed diabetes, and 56 men and 53 women had blood sugar levels that exceeded 120 mg/dl. Diabetes predisposed subjects to all of the 408 major cardiovascular disease outcomes. Diabetics had higher levels of fibrinogen, hypertension, hypertriglyceridemia, and obesity, but lower HDL cholesterol values. The influence of diabetes on cardiovascular disease was greatly dependent on these coexistent risk factors, but there was a substantial independent effect of glucose intolerance when all the standard risk factors had been taken into account. There was a rise in fibrinogen values throughout the range of blood sugar levels, which suggests a thrombogenic explanation for the unique diabetic effect. However, multivariate analysis indicates no further reduction in diabetic cardiovascular risk ratios after adjustment for fibrinogen; thus, there is a residual effect for glucose intolerance after all of the standard risk factors and fibrinogen have been taken into account.