Background. We previously reported that ranolazine improved myocardial ischemia during exercise myocardial perfusion imaging (MPI). Since the mechanism of reversible perfusion defects is different in exercise than vasodilator MPI, and based on the mechanism of action of ranolazine, we hypothesized that vasodilator stress MPI may fail to show improvement in myocardial perfusion pattern. Methods. Patients (n = 18) with known coronary artery disease and with reversible perfusion defects on a clinically indicated vasodilator stress MPI were re-studied 4 weeks after ranolazine (500-1000 mg PO BID) was added to their conventional treatment in an open-label trial. Perfusion pattern was assessed using automated methods. Results. The baseline left ventricular ejection fraction was 59% ± 14%. The total perfusion defect (measured by polar maps) was 22% ± 13% before and 21% ± 16% of LV myocardium after treatment (P = NS). The reversible defect size was 14% ± 10% before and 14% ± 11% of LV myocardium after treatment (P = NS). The automated-derived summed stress score was 12 ± 8 before and 12 ± 10 after treatment (P = NS) and the automated-derived summed difference score was 6 ± 5 before and 6 ± 5 after treatment (P = NS). Only 3 patients showed a decrease in reversible perfusion defect size with treatment. Conclusion. Vasodilator stress MPI failed to show improvement in perfusion pattern after ranolazine treatment in most patients with baseline reversible defects. This is consistent with the unique anti-ischemic mechanism of ranolazine, which acts on the late I Na channel. Copyright © 2011 American Society of Nuclear Cardiology.