Background Preliminary data suggests the absence of coronary artery calcification (CAC) excludes ischemic etiologies of cardiomyopathy. We prospectively validate and perform a systematic review to determine the utility of an Agatston score=0 to exclude the diagnosis of ischemic cardiomyopathy. Methods and results Patients with newly diagnosed LV dysfunction were prospectively enrolled. Patients underwent CAC imaging and were followed until an etiologic diagnosis of cardiomyopathy was made. Eighty-two patients were enrolled in the study and underwent CAC imaging with 81.7% patients having non-ischemic cardiomyopathy. An Agatston score=0 successfully excluded an ischemic etiology for cardiomyopathy with a specificity of 100% (CI: 74.7–100%) and a positive predictive value of 100% (CI: 85.0%–100%). A systematic literature review was performed and studies were deemed suitable for inclusion if: 1) patients with CHF, cardiomyopathy or LV dysfunction were enrolled, 2) underwent CAC imaging and patients were assessed for an Agatston score=0 or the absence of CAC, and 3) the final etiologic diagnosis (ischemic or non-ischemic) was provided. Eight studies provided sufficient information to calculate operating characteristics for an Agatston score=0 and were combined with our validation cohort for a total of 754 patients. An Agatston score=0 excluded ischemic cardiomyopathy with specificity and positive predictive values of 98.4% (CI: 95.6–99.5%), and 98.3% (CI: 95.5–99.5%), respectively. Conclusions In patients with cardiomyopathy of unknown etiology, an Agatston score=0 appears to rule out an ischemic etiology. A screening CAC may be a simple and cost-effective method of triaging patients, identifying those who do and do not need additional CAD investigations.