Purpose: To evaluate the cost effectiveness of DES compared to BMS using “real-world” data from a large cohort of prospectively followed patients. Methods: A one-year decision analytic model was used to estimate costs and effects (QALYs, revascularizations) for patients receiving DES or BMS. The Cardiac Care Network (CCN) of Ontario patient registry was modified to prospectively collect data regarding the utilization of coronary artery stents in the province. In addition to determining revascularization rates, other key clinical and variables were obtained from the registry to populate the decision model. The costs of revascularizations (PCI, CABG) were obtained from a hospital in southern Ontario and the stent costs were obtained from the device manufacturers. Utility values applied to time with angina, post revascularization, and otherwise healthy were estimated using results from the ARTS trial. Parameter uncertainty was assessed by means of probabilistic sensitivity analyses. Twenty-two groups based on diabetes status, lesion characteristics (based on total stent length and diameter), and a recent history of acute myocardial infarction within the previous 7 days, were analyzed. Results: In this economic evaluation, 7953 PCI cases with at least 9 months of follow-up were available for analysis. The incremental cost-effectiveness ratio of DES, compared to BMS, was most favourable in patients with diabetes that had long (> 20 mm) and narrow (< 2.5 mm) lesions ($223,000/QALY, $9,869/revacularization). This was also the subgroup with the greatest difference in revascularization rates (BMS: 20% vs. DES: 6%). Incremental cost effectiveness ratios were found to be greater than $500,000/QALY ($20,788/revascularization) in the majority of the patient cohorts (i.e. representing approximately 85% of all patients). Conclusions: The incremental cost-effectiveness of DES was high in all patient cohorts. The primary strength of the current analysis is that revascularization rates and other key model input variables are based upon data from a large sample of cases from a “real-world” setting and involves the analysis of almost all PCI cases in the province. Differences from other published economic analyses of DES and BMS, using clinical trial data, may be attributed to the poorer clinical benefits of BMS found in clinical trials compared to “real-world” clinical practice. This study highlights that cost-effectiveness results can vary considerably depending on the source of efficacy/effectiveness data.