Background: Differences in the prevalence and impact of hyperhomocytenemia on vascular disease between countries and races have been reported. Most studies have been undertaken in North American and European populations and the importance of plasma total homocysteine (tHcy) level as a risk factor for coronary artery disease in the Middle East particularly in Iran, however, is not known.  Objective: To determine the association of hyperhomocysteinemia with coronary artery disease in Shiraz population, a city in the South West of Iran.  Method: A case-control study was conducted in 195 men with angiographically defined coronary artery disease and 201 healthy controls. Plasma tHcy concentrations were analyzed in baseline samples by high performance liquid chromatography. Results: Geometric mean of plasma tHcy was significantly higher in patients (10.6±5.2 mmol/l) than in control (7.9±3.1 mmol/l) group (p<0.001). Comparing the top fifth (quintile), of the plasma tHcy distribution to the bottom fifth, the adjusted odds ratio of coronary artery disease was 2.3 (95% CI 1.0–5.5) and there was a positive trend of increasing risk across quintiles of the plasma tHcy distribution (p=0.02).Conclusion: High plasma tHcy is associated with coronary artery disease in Iranians living in Shiraz.