Coronary artery disease (CAD) is emerging as a major public health concern in most developing countries. Further conventional risk factors for CAD do not solely account for the increased mortality, particularly in Asians. Recently, increased plasma homocysteine is being considered as a risk factor, but the strength of relationship and interaction of plasma homocysteine with other risk factors is yet obscure. In this study, the association of plasma homocysteine with CAD and other risk factors was estimated.In the present study, 100 patients of CAD and 50 controls of both sexes were included. Plasma total homocysteine (tHcy) concentrations were measured using reverse phase high-performance liquid chromatography.Plasma homocysteine concentrations were significantly raised in cases as compared to age-matched controls (16.57±6.86 and 11.47±5.19 μmol/l, p<0.001). On calculating relative risk (RR) of each factor by univariate analysis smoking, hypertension, plasma cholesterol and homocysteine appeared to be significant risk factors. However, on applying multiple logistic regression only the latter three emerged as independent risk factors (p<0.005). Further, strong interactive effects were observed between homocysteine levels and increasing age, hypertension and smoking.An increase in plasma homocysteine concentration confers an independent risk for CAD. It further increases the risk associated with increasing age, smoking and hypertension. Thus, increased homocysteine concentrations are a significant medical problem and effective strategies are urgently required to counter this challenge.