Study objective Coronary artery calcium score (CACS) is a well-established test for risk stratifying asymptomatic patients. Recent studies also indicate that CACS may accurately risk stratify stable patients presenting to the emergency department (ED) with acute chest pain; however, many were underpowered. The purpose of this systematic review and meta-analysis is to evaluate the prognostic value and accuracy of a zero (normal) CACS for identifying patients at acceptable low risk for future cardiovascular events who might be safely discharged home from the ED. Methods We searched multiple databases for longitudinal studies of CACS in symptomatic patients without known coronary artery disease that reported major adverse cardiovascular events (MACEs), including death and myocardial infarction. Pooled risk ratios, sensitivity, specificity, and likelihood ratios were analyzed. Results Eight studies evaluated 3,556 patients, with a median follow-up of 10.5 months. Pooled prevalence of zero CACS was 60%. Patients with CACS=0 had a significantly lower risk of cardiovascular events compared with those with CACS greater than 0 (MACEs: relative risk 0.06, 95% confidence interval 0.04 to 0.11, I2=0%; death/myocardial infarction: relative risk 0.19; 95% confidence interval 0.08 to 0.47, I2=0%). The pooled event rates for CACS=0 (MACEs 0.8%/year; death/myocardial infarction 0.5%/year) were significantly lower than for CACS greater than 0 (MACEs 14.6%/year; death/myocardial infarction 3.5%/year). Analysis of summary testing parameters showed a sensitivity of 96%, specificity of 60%, positive likelihood ratio of 2.36, and negative likelihood ratio of 0.07. Conclusion Acute chest pain patients without history of coronary artery disease, ischemic ECG changes, or increased cardiac enzyme levels commonly have a CACS of zero, with a very low subsequent risk of MACEs or death or myocardial infarction. This meta-analysis proffers the potential role of initial CACS testing for avoiding unnecessary hospitalization and further cardiac testing in acute chest pain patients with a CACS of zero.