OBJECTIVES: To evaluate the economic attractiveness of Endeavor vs. Cypher drug-eluting stents (DES) in the ENDEAVOR III clinical trial. METHODS: We analyzed case report form information from subjects randomized to receive Endeavor (n=323) vs. Cypher (n=113) stents, using quality of life adjustment and Medicare cost weights applied from secondary sources, and a $2100 cost for stents. We compared differences in outcomes and costs; and evaluated cost-effectiveness through 3-years follow-up (1080 days). RESULTS: The use of Endeavor vs. Cypher stents reduced the 3-year rates per 100 subjects of death or myocardial infarction (MI) (3.9 vs. 10.8; difference, -6.9; 95% confidence interval [CI], -0.8 to -9.9; p=.028), with no difference in target vessel revascularization rates (17.9 vs. 12.2; difference, 5.7; 95% CI, -3.9 to 15.1; p=.23), but greater use of coronary artery bypass graft surgery (3.5 vs. 0.0; difference 3.5; 95% CI, 1.3 to 5.7; p=.002). After discounting at 3% per annum, total medical costs for Endeavor vs. Cypher were similar ($23,353 vs. $21,657; difference, $1696; 95% CI, -$1089 to $4482, p=.23), and the 3-year cost-effectiveness ratio was $57,002 per quality-adjusted life year. CONCLUSIONS: Use of Endeavor vs. Cypher led to reductions in death or MI, with no differences in other outcomes. These findings are unexpected in DES comparisons. If future trials observe similar differences, the use of Endeavor vs. Cypher will be economically attractive by conventional standards.