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Patients with refractory angina (RA) have limited therapeutic options and significant limitations in their quality of life. Ranolazine is approved for patients with chronic stable angina but has not been studied in patients with RA. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness in RA patients. In a dedicated RA clinic using an extensive prospective database, 100 patients were enrolled. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 1, 6, and 12 months. Overall 43% of patients had a ≥2 class improvement in angina. At 1 year, 57% patients remained on ranolazine (91.2%; 500 mg BID), including 58% with a ≥2 class improvement in angina. Reasons for discontinuation included: side effects (n = 16), major adverse cardiac events (n = 10), cost (n = 5), ineffective (n = 6), cost and ineffective (n = 3), and unknown (n = 3). In conclusion, ranolazine is an effective antianginal therapy in patients with RA; still at 1 year only 57% of patients remained on ranolazine because of side effects, suboptimal effectiveness, cost, or progression of disease.