It has been postulated that the accumulation of homocysteine in plasma may induce arteriosclerosis. In order to explore the possible contribution of homocysteine to the occurrence of macroangiopathy in patients with non-insulin-dependent diabetes mellitus, the concentrations of total homocysteine in plasma were determined in 52 diabetic patients with clinical macroangiopathy, 84 diabetic patients without macroangiopathy, and 57 non-diabetic control subjects. The levels of total homocysteine in plasma were significantly higher in diabetic patients with macroangiopathy (10.8 +/- 3.8 nmol/ml) than in those without macroangiopathy (8.3 +/- 3.1 mmol/ml, P < 0.001) or non-diabetic subjects (7.5 +/- 2.1 nmol/ml, P < 0.001). Among all diabetic patients, multiple logistic regression analysis after adjustment for age, sex, and systolic blood pressure revealed that high levels of plasma homocysteine were significantly associated with the presence of diabetic macroangiopathy (P = 0.01). By an intramuscular injection of 1000 micrograms methylcobalamin daily for 3 weeks, the plasma levels of homocysteine in 10 diabetic patients were significantly decreased (14.7 +/- 7.5 vs. 10.2 +/- 6.0 nmol/ml, P < 0.01). Our results suggest that plasma homocysteine levels could be one of a number of independent risk factors for macroangiopathy in patients with diabetes mellitus and that they can be reduced by parenteral treatment with methylcobalamin.