Background-The coronary artery calcium (CAC) score predicts future coronary heart disease (CHD) events and could be used to guide primary prevention interventions, but CAC measurement has costs and exposes patients to low-dose radiation. Methods and Results-We estimated the cost-effectiveness of measuring CAC and prescribing statin therapy based on the resulting score under a range of assumptions using an established model enhanced with CAC distribution and risk estimates from the Multi-Ethnic Study of Atherosclerosis. Ten years of statin treatment for 10 000 55-year-old women with high cholesterol (10-year CHD risk, 7.5%) was projected to prevent 32 myocardial infarctions, cause 70 cases of statin-induced myopathy, and add 1108 years to total life expectancy. Measuring CAC and targeting statin treatment to the 2500 women with CAC>0 would provide 45% of the benefit (+501 life-years), but CAC measurement would cost $2.25 million and cause 9 radiation-induced cancers. Treat all was preferable to CAC screening in this scenario and across a broad range of other scenarios (CHD risk, 2.5%-15%) when statin assumptions were favorable ($0.13 per pill and no quality of life penalty). When statin assumptions were less favorable ($1.00 per pill and disutility=0.00384), CAC screening with statin treatment for persons with CAC>0 was cost-effective (<$50 000 per quality-adjusted life-year) inthis scenario, in 55-year-old men with CHD risk 7.5%, and in other intermediate risk scenarios (CHD risk, 5%-10%). Our results were critically sensitive to statin cost and disutility and relatively robust to other assumptions. Alternate CAC treatment thresholds (>100 or >300) were generally not cost-effective. Conclusions-CAC testing in intermediate risk patients can be cost-effective but only if statins are costly or significantly affect quality of life. (Circ Cardiovasc Qual Outcomes. 2014;7:276-284.). © 2014 American Heart Association, Inc.