Background: Myocardial ischemia may be caused by microvascular disease. The ratio of the maximal possible coronary blood flow to the resting coronary blood flow is termed "the coronary flow reserve" (CFR), which may be assessed noninvasively via dipyridamole stress echocardiography (DSE). Ranolazine is an anti-ischemic agent whose effect on the coronary flow is poorly known. Purpose: We sought to assess temporal variations in the CFR after and before ranolazine administration in a real clinical practice setting among patients with angina and non-obstructive epicardial coronary artery disease. Methods: Seven patients were enrolled, and their demographic, electrocardiographic, and laboratory data were recorded. The CFR was calculated in the anterior descending coronary artery. The definition of abnormal microcirculation was a cutoff value under 2.5. Treatment lasted for 3 months, after which time the same response variables as before were recorded. A general linear model was used to assess whether there was a difference between the pre-and post-administration of ranolazine. Results: Seven patients were evaluated. At follow-up, there was no discontinuation or side effect. The CFR significantly increased with time (F1,6 = 6.909; P = 0.039). Initially, the mean (± 1 SD) value was 1.85 (± 0.34), which rose up to 2.21 (± 0.31) after the 3-month treatment period. Conclusions: Ranolazine might have beneficial effects on the CFR as assessed by DSE in patients with angina and non-obstructive epicardial coronary artery disease.