Objective: To investigate the relationship between serum interleukin (IL)-33, osteoprotegerin and the severity of coronary artery disease in patients with coronary heart disease, and analyze the correlation between IL-33 and osteoprotegerin. Methods: Two hundred and nineteen patients with coronary heart disease from April 2018 to June 2019 in Dalian Friendship Hospital were selected. The percutaneous coronary angiography was performed in all patients. Among them, acute myocardial infarction (AMI) was in 59 cases (AMI group), unstable angina pectoris (UAP) in 55 cases (UAP group), stable angina pectoris (SAP) in 55 cases (SAP group), and basically normal result was in 50 cases (control group). Serum IL-33 and osteoprotegerin levels were measured by enzyme-linked immunosorbent assay (ELISA), and the severity degree of coronary artery disease was assessed by Gensini scoring system. Results: The IL-33 in SAP group, UAP group and AMI group was significantly higher than that in control group: (330.42 ± 82.56), (363.54 ± 61.36) and (448.62 ± 71.60) ng/L vs. (275.96 ± 74.34) ng/L, IL-33 in AMI group was significantly higher than that in SAP group and UAP group, and there were statistical differences (P<0.05). The osteoprotegerin in UAP group and AMI group was significantly higher than that in control group: (481.35 ± 101.68) and (558.29 ± 136.45) ng/L vs. (392.21 ± 109.57) ng/L, osteoprotegerin in AMI group was significantly higher than that in SAP group and UAP group: (558.29 ± 136.45) ng/L vs. (436.13 ± 121.84) and (481.35 ± 101.68) ng/L, and there were statistical differences (P<0.05). The Gensini score in SAP group, UAP group and AMI group was significantly higher than that in control group: (23.31 ± 7.88), (44.37 ± 14.15) and (90.20 ± 42.01) scores vs. (7.17 ± 4.85) scores, Gensini score in UAP group was significantly higher than that in SAP group, Gensini score in AMI group was significantly higher than that in SAP group and UAP group, and there were statistical differences (P<0.05). Pearson correlation analysis result showed that serum IL-33 and osteoprotegerin levels were positively correlated with Gensini score (r = 0.588 and 0.420, P<0.01), and serum IL-33 level was positively correlated with osteoprotegerin level (r = 0.718, P<0.01). The receiver operating characteristic curve analysis result showed that the area under curve of IL-33 for the diagnosis of AMI was 0.887 (95% CI 0.839 to 0.935, P<0.01), and the area under curve of osteoprotegerin for diagnosis of AMI was 0.754 (95% CI 0.682 to 0.825, P<0.01). Conclusions Serum IL-33 and osteoprotegerin levels are elevated in patients with coronary heart disease, and their elevated levels are positively correlated with the severity and instability of coronary artery disease and have a certain diagnostic value for AMI.