Abstract Background High resting coronary flow velocity (CFV) in the mid-distal left anterior descending coronary artery (LAD) can be easily assessed with transthoracic echocardiography (TTE) and is a predictor of worse survival. Purpose In this study, we sought to assess the relationship between resting CFV, coronary flow velocity reserve (CFVR), and outcome in patients without inducible regional wall motion abnormality during stress echo (SE). Methods In a prospective multicenter study design, we enrolled 6,887 patients (age 65±11 years, 3,838 men, 1,963 diabetics), with left ventricular ejection fraction (LVEF) ≥50% referred for SE. Recruitment (years 2004-2022) involved 7 accredited laboratories, with inter-observer variability <10% for CFV measurement at study entry. Baseline peak diastolic CFV (abnormal value >32 cm/s) was obtained by pulsed-wave Doppler in mid-distal LAD. Coronary flow velocity reserve (CFVR, abnormal value ≤2.0) was assessed with dipyridamole. All-cause death was the only end-point. Results The mean CFV of LAD was 30±11 cm/s. The mean CFVR was 2.37±0.58. During a median follow-up of 6.0±4.2, 1,015 (15%) patients died. At Cox analysis, resting CFV >32 cm/s independently predicted mortality together with CFVR <2, age, diabetes, previous myocardial infarction, history of coronary surgery and LVEF. Resting CFV allowed effective risk stratification either in diabetics and nondiabetics although the difference in survival based on resting CFV was more marked in the former (Figure). In addition, it added significant (p<0.0001) prognostic information to CFVR result in the diabetic, but not in the non-diabetic population (Figure). Conclusion High resting CFV with TTE in mid-distal LAD predicts worse survival in patients without inducible ischemia. The value is independent and additive to CFVR in diabetic patients. The combination of high resting CFV-low CFVR is associated with worse survival.