Objective To investigate the changes of serum homocysteine (Hcy) and cystatin C (CysC) levels in patients with coronary artery disease (CHD) and its clinical significance. Methods The serum levels of Hcy and CysC in 218 cases of coronary heart disease patients and 129 healthy controls were detected and their relations were then analyzed. Results The serum levels of Hcy and CysC in CHD group were higher than that of control group (P<0.01), and the positive rate in CHD group was significantly higher than that in control group (P<0.01), while the positive rate of combined detection of Hcy and CysC was significantly higher than that of single detection(P<0.01). The serum Hcy and CysC to diagnose coronary heart disease had a high specificity (92.2% and 97.7% respectively) and positive predictive value (89.2% and 96.1% respectively), while the sensitivity (38.1% and 33.9% respectively) and negative predictive value (46.9% and 46.7% respectively) were not high. The combined detection could significantly improve the diagnostic sensitivity to 51.8%. The serum Hcy levels were positively correlated with CysC levels (r=0.363, P<0.01). Conclusion The serum Hcy and CysC levels closely associate with coronary heart disease. The combined detection of Hcy and CysC has important clinical significance in the diagnosis, treatment and prognosis of patients with coronary heart disease.