Background: Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily and plays an important regulatory role in the skeletal, immune, and vascular systems. Intermediate coronary artery lesions that have a diameter stenosis of approximately 20%-70% might cause serious consequences. However, the prognostic value of plasma OPG levels in patients with intermediate coronary artery lesions has been less reported. Hypothesis: We hypothesized that OPG is a predictive marker of prognosis of intermediate coronary artery lesions. Methods: A prospective study was performed on 890 patients with intermediate (20%-70%) coronary lesions. The median age was 62 years (25th and 75th percentiles, 55 and 70 years, respectively) and 67.2% were male. Fasting blood was sampled at baseline. The primary clinical endpoint was a composite of readmission due to angina pectoris, nonfatal myocardial infarction, revascularization, and cardiovascular death. Results: During a median follow-up of 24 months, events occurred in 11.1% of the patients. Of these patients, 7.9% were readmitted for angina pectoris, 1.5% received revascularization, 0.7% suffered nonfatal myocardial infarction, and 1.0% died. The plasma levels of OPG (median, 5304.7 pg/mL vs 2993.4 pg/mL, P < 0.001) and high-sensitivity C-reactive protein (median, 4.8 mg/L vs 2.6 mg/L, P < 0.001) were higher in patients with events than those without events. After adjusting for traditional risk factors such as age, gender, smoking, hypertension, diabetes, dyslipidemia, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, percent area stenosis, and drug administration, a multivariate Cox proportional hazard analysis showed that higher OPG levels were an independent predictive factor of the composite clinical endpoint (hazard ratio: 2.49, 95% confidence interval: 1.26-4.89, fourth quartile vs first quartile). Conclusions: The higher level of OPG is an independent predictive factor of prognosis in patients with intermediate coronary lesions.