BACKGROUND: Evaluation of acute chest pain is highly variable. OBJECTIVE: To evaluate the cost-effectiveness of strategies using cardiac markers and noninvasive tests for myocardial ischemia. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Prospective data from 1066 patients with chest pain and from the published literature. TARGET POPULATION: Patients admitted with acute chest pain. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Creatine kinase (CK)-MB mass assay alone; CK-MB mass assay followed by cardiac troponin I assay if the CK-MB value is normal; CK-MB mass assay followed by troponin I assay if the CK-MB value is normal and electrocardiography shows ischemic changes; both CK-MB mass and troponin I assays; and troponin I assay alone. These strategies were evaluated alone or in combination with early exercise testing. OUTCOME MEASURES: Lifetime cost, life expectancy (in years), and incremental cost-effectiveness. RESULTS OF BASE-CASE ANALYSIS: For patients 55 to 64 years of age, measurement of CK-MB mass followed by exercise testing in appropriate patients was the most competitive strategy ($43000 per year of life saved). Measurement of CK-MB mass followed by troponin I measurement had an incremental cost-effectiveness ratio of $47400 per year of life saved for patients 65 to 74 years of age; it was also the most cost-effective strategy when early exercise testing could not be performed, CK-MB values were normal, and ischemic changes were seen on electrocardiography. RESULTS OF SENSITIVITY ANALYSIS: Results were influenced by age, probability of myocardial infarction, and medical costs. CONCLUSIONS: Measurement of CK-MB mass plus early exercise testing is a cost-effective initial strategy for younger patients and those with a low to moderate probability of myocardial infarction. Troponin I measurement can be a cost-effective second test in higher-risk subsets of patients if the CK-MB level is normal and early exercise testing is not an option.