Patients with diabetes mellitus are prone to cardiovascular disease and risk factors presumably unrelated to diabetes, such as hyperhomocysteinemia, may be involved in the atherothrombotic process in these subjects. Plasma homocysteine levels are usually normal in diabetes, although both lower and higher levels have been reported. This has been ascribed to hyperfiltration and renal dysfunction or low folate status, respectively. Insulin resistance does not appear to be a major determinant of plasma homocysteine level. Hyperhomocysteinemia has been associated with microalbuminuria and retinopathy in type 1 and type 2 diabetes. In patients with type 2 diabetes, plasma homocysteine concentration has also been shown to be related to macrovascular disease and death. This relation seems to be stronger in diabetics than in subjects without diabetes. The underlying pathophysiological mechanism of this increased vascular risk remains unexplained but may relate to worsening of endothelial dysfunction or structural vessel properties. Because homocysteine and diabetes have an apparent synergistic negative vascular effect, patients with diabetes are good candidates for screening and treatment with folic acid until the results of ongoing clinical trials are available.