Objective: Osteoprotegerin (OPG) strongly inhibits bone resorption and may also serve as a vascular calcification inhibitor. However, recent studies have indicated that high plasma OPG is a strong predictor of cardiovascular disease (CVD) and mortality. To evaluate this capability, the data concerning OPG as a CVD predictor was gathered through a systematic literature review.Design and methods: Studies investigating OPG as a predictor of CVD or mortality were extracted from Medline and the Cochrane Library, retrieving 187 articles. Non-relevant articles were excluded, resulting in a total of 45 articles. After thorough evaluation of the abstracts, only eight prospective studies containing a follow-up period with a clinical emphasis on CVD were eligible for the literature review.Results: All studies except one confirmed that OPG measurement adds important prognostic information to the existing markers of CVD and mortality in high-risk populations. Hazard ratios emphasized the significant correlation between plasma OPG concentration and mortality. Due to methodological problems (e.g., population investigated, measurement principle, and statistics performed), meta-analysis could not be performed. As only one study was conducted in a healthy cohort, the results cannot per se be extrapolated to the general population.Conclusion: The combined results support plasma OPG as an independent predictor of CVD and mortality in high-risk populations. However, more longitudinal studies in general cohorts are needed before the use of plasma OPG can be evaluated in this regard.