AIMS: An increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascularization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history and predictors of adverse outcome, these patients have been considered at high risk for early mortality. METHODS AND RESULTS: The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200 patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4% prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died (20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0-16, 14.7% over 9). By Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all-cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF. CONCLUSION: Long-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life.