The optimal diagnostic evaluation of patients presenting to the emergency department (ED) with chest pain but without myocardial infarction or unstable angina is controversial. We performed a prospective, nonrandomized, observational study of 1,195 consecutive patients presenting to the ED with chest pain but who had normal or nondiagnostic electrocardiograms and negative cardiac biomarkers. Patients (mean ± SD age 61 ± 15 years; 55% women) were admitted to the hospital and a standard protocol for evaluation and treatment was suggested. The use of stress myocardial perfusion imaging (MPI) or cardiac catheterization during their index hospitalization, and the 3-month incidence of coronary angiography, percutaneous cardiac intervention, coronary artery bypass surgery, re-presentation to our institution’s ED for chest pain, myocardial infarction, or death were followed. Five hundred nine of 1,195 patients (43%) underwent provocative stress MPI during their index hospitalization; 37% had perfusion defects (predominantly ischemia). Fifty-six of 1,195 patients (4%) underwent cardiac catheterization without stress MPI for their primary diagnostic evaluation. Six hundred thirty of 1,195 patients (53%) had neither MPI or cardiac catheterization during their index hospitalization. During the 3-month follow-up period, patients with a normal stress perfusion study during their index hospitalization had fewer return visits (4%) compared with patients with abnormal perfusion studies (19%), those who underwent catheterization directly (16%), or patients with no initial diagnostic evaluation (15%) (p <0.001). In addition, patients who had a diagnostic evaluation during their index hospitalization had a lower incidence of either acute myocardial infarction (0.9% vs 2.1%) or death (0.4% vs 3.0%, p <0.001) in the 3-month follow-up period. Accordingly, we strongly advocate provocative stress MPI early after presentation for chest pain in all patients with risk factors for coronary artery disease.