Objective: We derived a clinical decision rule to determine which emergency department (ED) patients with chest pain and possible acute coronary syndrome (ACS) require chest radiography. Methods: We prospectively enrolled patients over 24 years of age with a primary complaint of chest pain and possible ACS over a 6-month period. Emergency physicians completed standardized clinical assessments and ordered chest radiographs as appropriate. Two blinded investigators independently classified chest radiographs as "normal," "abnormal not requiring intervention" and "abnormal requiring intervention," based on review of the radiology report and the medical record. The primary outcome was abnormality of chest radiographs requiring acute intervention. Analyses included interrater reliability assessment (with κ statistics), univariate analyses and recursive partitioning. Results: We enrolled 529 patients during the study period between Jul. 1, 2007, and Dec. 31, 2007. Patients had a mean age of 59.9 years, 60.3% were male, 4.0% had a history of congestive heart failure and 21.9% had a history of acute myocardial infarction. Only 2.1% (95% confidence interval [CI] 1.1%-3.8%) of patients had radiographic abnormality of the chest requiring acute intervention. The κ statistic for chest radiograph classification was 0.81 (95% CI 0.66-0.95). We derived the following rule: patients can forgo chest radiography if they have no history of congestive heart failure, no history of smoking and no abnormalities on lung auscultation. The rule was 100% sensitive (95% CI 32.0%-40.4%) and 36.1% specific (95% CI 32.0%-40.4%). Conclusion: This rule has potential to reduce health care costs and enhance ED patient flow. It requires validation in an independent patient population before introduction into clinical practice.