Obesity, hypertension, diabetes mellitus and smoking are all well known risk factors for cardiovascular disease. However, the link between these risk factors, plasma insulin and endothelin-1(ET-1) as well as cardiovascular diseases remains to be undetermined and must be clarified. So, the current work was carried on 120 men. Their ages ranged between 32-64 years with a mean value 59±9.5, They were classified into 6 groups ;control, obese, hypertensive, uncontrolled, controlled diabetics and smokers. The results of this work showed that plasma C-peptide and insulin were significantly increased in obese, uncontrolled and controlled diabetic groups (p<0.05) compared with the control group. Moreover, plasma insulin was significantly increased in, hypertensive group compared with the control group(p<0.005) .In addition, plasma ET-1 was significantly increased in all risky groups compared with the control group (p<0.05). Comparative study of controlled versus uncontrolled diabetic group, plasma C-peptide, insulin and ET-1 were all significantly decreased(P1<0.05).On the otherhand , correlation study showed that; plasma insulin was significantly positive correlated with plasma ET-1 in obese (r=0.514 p<0.05), hypertensive (r=0.555 p<0.05), uncontrolled diabetes mellitus (r=0.510 p<0.05) and controlled diabetes mellitus groups (r= 0,496 p<0.05) while nonsignificantly positive correlated with ET-1 in smoking group. We could conclude that, hyperinsulinemia will sign a danger signal for the increase of plasma ET-1 and subsequent endothelial dysfunction in all risky subjects . So, they are more prone to ischemic heart disease . However, further study was needed using ET-1 antagonists on its receptors which may be of help to abolish or at least to minimize its pathophysiological effects on blood vessels. This is may be benefit for clinical intervention