There has been more and more evidence to confirm the essential role of inflammatory processes in the development of coronary artery disease (CAD). Interleukin‐21 (IL‐21), the most recently discovered CD132‐dependent cytokine, plays a key role in regulating inflammation. The aim of the study was to understand the effect of peripheral IL‐21 on the pathogenesis and progression of CAD. Serum level of IL‐21 in 92 CAD patients and 73 controls was measured by the enzyme‐linked immunosorbent assay. Data showed that IL‐21 expression was significantly increased in CAD than in controls (p < 0.001). Interestingly, when comparing IL‐21 level with different genders, male subjects revealed higher IL‐21 than female subjects (p = 0.024). Also, we observed that patients with hypertension had upregulated level of serum IL‐21 (p = 0.002). Moreover, serum level of IL‐21 was positively correlated with total cholesterol level (p = 0.015) or low‐density lipoprotein cholesterol (p = 0.0009) of CAD cases. In addition, we analyzed IL‐21 level with the severity of CAD, and identified that cases with 3‐vessel affected had significantly elevated level of IL‐21 than those with 1‐vessel or 2‐vessel affected. These data suggested that serum level of IL‐21 may be closely associated with the development and progression of CAD.