Background: In cases with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), attention should be given to the risk of cardiovascular diseases, which are responsible for an excess burden of morbidity & mortality. In cases with RA and SLE, the cardiovascular system (CVS) should be evaluated for early detection of subclinical cardiovascular affection. Objective: To assess serum interleukin-21 level and IL-21 genetic polymorphism association with the CVS risk in cases with RA and SLE. Patients and methods: Seventy patients with RA, seventy patients with SLE and seventy matched controls were included in the study. Measurements of serum IL-21 levels were conducted by using ELISA procedure, and polymerase chain reaction (RT-PCR) was used to determine the genotypes. Cardiovascular assessment was done by: electrocardiography, transthoracic echocardiography, evaluation of carotid atherosclerosis by intima media thickness (IMT) of the carotid artery and evaluation of endothelial function by flow mediated dilation (ED-FMD) of the brachial artery. Results: Serum interleukin-21 level was significantly higher in cases compared to healthy controls (HC), with significant elevation in clinically active patients. A significant relationship between serum IL-21 level with activity score, ejection fraction, intima media thickness, cholesterol, low density lipoprotein (LDL) and flow mediated dilatation was found. Patients with rs6822844 GT and TT haplotypes showed higher frequency of subclinical cardiovascular abnormalities in RA (p=0.0002, 0.01) and in SLE (p=0.001, 0.025) patients' groups respectively. Conclusion: IL-21 may be a potential biomarker of cardiovascular risk in RA and SLE, and could be used as a possible target for new therapeutic agents. IL-21 polymorphism was significantly accompanied by inherited predisposition to RA and SLE and their associated cardiovascular morbidity.