BACKGROUND: Sodium– glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. METHODS AND RESULTS: We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08– 2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, −0.18 to 0.21) or placebo groups: 0.06 (95% CI, −0.15 to 0.27), with no treatment effect −0.05 (95% CI, −0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A_1c by 0.76% (95% CI, 1.0– 0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7– 2.6; P<0.001). CONCLUSIONS: Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. REGISTRATION: URL: https://clini​caltr​ialsr​egist​er.eu/; Unique identifier: 2016-003743-10.