We previously reported that ranolazine improves exercise myocardial perfusion. Ranolazine ameliorates myocardial ischemia by augmenting myocardial blood flow; likely by a reduction in the extravascular compression of small vessels. We hypothesized that ranolazine could improve left ventricular (LV) dyssynchrony as assessed by phase analysis of gated single photon emission computed tomographic myocardial perfusion imaging. Patients (n = 32) with known or suspected coronary artery disease and reversible perfusion defects on a clinically indicated stress myocardial perfusion imaging were restudied 4 weeks after ranolazine (500 to 1,000 mg orally twice daily) was added to their conventional treatment in an open-label trial (data previously reported). The LV systolic and diastolic dyssynchrony indexes were obtained using automated phase analysis before and after ranolazine. No significant changes were found in the heart rate or blood pressure (at rest or during stress) after treatment. The perfusion pattern improved in 13 of 18 patients who had undergone exercise testing, but in only 3 of 14 patients who had undergone vasodilator stress testing. No significant changes were seen in the LV ejection fraction or volume after treatment. The systolic and diastolic LV dyssynchrony improved after ranolazine therapy; there was a significant decrease in the systolic phase SD (21 ± 17 vs 18 ± 13, p = 0.04), systolic bandwidth (69 ± 60 vs 53 ± 38, p = 0.03), diastolic SD (29 ± 18 vs 24 ± 15, p = 0.047) and diastolic bandwidth (91 ± 61 vs 72 ± 45, p = 0.02). In conclusion, the present study is the first to show improvements in diastolic and systolic LV synchrony with ranolazine as measured by automated phase analysis of gated single photon emission computed tomographic myocardial perfusion imaging.