Background: Fibroblast growth factor 21 (FGF21) is an emerging metabolic regulator. Circulating levels of FGF-21 are found in obese individuals and subjects with metabolic syndrome or type 2 diabetes and are closely associated with obesity and cardiovascular risk. However data are limited for advanced outcomes such as coronary heart disease (CHD). Previous studies of FGF21in CHD have been largely confounded by obesity and did not describe FGF21 level in CHD in terms of severity. Aim of work: Investigating the associations between serum FGF-21 in CHD subjects strictly matched for BMI. It also investigated the possible association between serum FGF21 and the coronary angiographic findings in terms of number of coronary vessels affected. Associations between serum FGF21, in CHD individuals, with diabetes, hypertension, or both were also addressed. Methods: Seventy patients were recruited from individuals admitted to the Critical Care Unit, for coronary angiography to assess CHD. Twelve (age, sex and body mass index (BMI) matched) apparently healthy individuals were also included in the present study. After coronary angiography the patients group were classified into: Sub-group (A): Coronary Artery Disease patients without DM or hypertension; Sub-group (B): Coronary Artery Disease patients with DM and/or hypertension; Sub-group (C): Subjects showing normal angiography but suffering from DM and/ or hypertension. Also CHD patients were classified according to number of stenosed coronary vessels into 3 subgroups with 1, 2 and multi-vessel affection. Fasting serum levels of FGF21, glucose, insulin and lipid profile was estimated. Results: The present results illustrated an increase in the median levels of serum FGF-21 in CHD patients versus the control group. A significant increase in the median levels of FGF-21 was detected in CHD patients with two vessel and multi-vessel affection compared to the control group and the one-vessel affecting group. Serum concentrations of FGF-21 were also increased in CHD subjects with diabetes or hypertension in comparison to diabetic and hypertensive patients not suffering from CHD. There was a highly significant positive correlation between serum levels of FGF-21 and each of BMI (r=0.7, p > 0.001), SBP(r=0.63, p > 0.001), and DBP (r=0.67, p > 0.001). A weakly significant positive correlation was also found between serum levels of FGF-21 and each of TAG (r=0.223, p > 0.05) and serum levels of LDL-c (r=0.223, p > 0.05). A weakly significant negative correlation was also found between serum levels of FGF-21 and serum levels of HDL-c (r=0.23, p > 0.05). Multi–variate logistic regression analysis revealed that the SBP was an independent risk factor for CHD. ROC curve analysis indicated that the optimum cut off value for plasma FGF 21 level in patients with CHD versus non CAD was 256 which gives 60% sensitivity and 63.64% specificity. Conclusion: This study provides clinical evidence revealing that serum concentrations of FGF-21 are increased in CHD subjects with diabetes or hypertension in comparison to diabetic and hypertensive patients not suffering from CHD. Our data suggest that serum concentrations of FGF21 in humans are not related to insulin secretion, but rather to lipid metabolism. SBP appears to be strongly associated with serum FGF21 in CHD subjects. The consistent increase in FGF21 seen in human CHD patients and apparent significant difference between severity classified subgroups raises the intriguing possibility that FGF21 could be a biomarker for CHD and may be used to asses severity of CHD.