Background Hyperhomocysteinemia confers an increased risk of coronary artery disease, stroke, and deep vein thrombosis, and is a strong predictor of mortality among patients with ischemic heart disease. Purpose To determne the long term clinical outcome of patients with risk factors to atherosclerosis with high concentrations of homocysteine (Hcy). Methods 89 patients with one or more risk factors for atherosclerosis, whose plasma total Hcy concentrations were measured, were followed for 5 years. Patients were interviewed and underwent a clinical examination in the outpatient clinic. Their medical records were reviewed in the last 5 years including smoking habits, medications, other diseases (hypertension, diabetes mellitus, hyperlipidemia) and their management. SPSS was used to describe and explore possible relationships between Hcy concentration, other diseases, medications and the clinical long term outcome. Results All men with normal Hcy concentrations (10.76±1.71μmol/L) survived during the 5 years' follow up, while 5 of the men with high Hcy concentrations (21.27±5.37μmol/L), died (17%) (P< 0.05). In women Hcy concentration did not affect survival. No association was found between diabetes mellitus, hypercholesterolemia, hypertension and Hcy. Long term treatment with Beta Blockers, ACE inhibitors, Calcium Channel blockers, and especially with Aspirin prevented death and changed the natural history of patients with high Hcy concentrations (P < 0.05). Conclusions Hyperhomocysteinemia may have an effect on survival in men. Long term treatment with Beta Blockers, ACE inhibitors, Calcium Channel Blockers, and especially with Aspirin prevented death and changed the natural history of patients with high Hcy concentrations.