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Objective: This review evaluates costs and benefits associated with acquiring, implementing, and operating clinical decision support systems (CDSSs) to prevent cardiovascular disease (CVD)., Materials and Methods: Methods developed for the Community Guide were used to review CDSS literature covering the period from January 1976 to October 2015. Twenty-one studies were identified for inclusion., Results: It was difficult to draw a meaningful estimate for the cost of acquiring and operating CDSSs to prevent CVD from the available studies ( n  = 12) due to considerable heterogeneity. Several studies ( n  = 11) indicated that health care costs were averted by using CDSSs but many were partial assessments that did not consider all components of health care. Four cost-benefit studies reached conflicting conclusions about the net benefit of CDSSs based on incomplete assessments of costs and benefits. Three cost-utility studies indicated inconsistent conclusions regarding cost-effectiveness based on a conservative $50,000 threshold., Discussion: Intervention costs were not negligible, but specific estimates were not derived because of the heterogeneity of implementation and reporting metrics. Expected economic benefits from averted health care cost could not be determined with confidence because many studies did not fully account for all components of health care., Conclusion: We were unable to conclude whether CDSSs for CVD prevention is either cost-beneficial or cost-effective. Several evidence gaps are identified, most prominently a lack of information about major drivers of cost and benefit, a lack of standard metrics for the cost of CDSSs, and not allowing for useful life of a CDSS that generally extends beyond one accounting period., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2017. This work is written by US Government employees and is in the public domain in the US.)