Abstract Background Reduced left ventricular ejection fraction (LVEF) has been used as a key criterion for the management of mitral regurgitation (MR) in patients with heart failure (HF), including the decision about mitral valve repair. However, LVEF, not taking into account mitral regurgitant volume, may be an imprecise predictor of outcome in HF patients with MR. Conversely, the estimation of the forward volume through the LV outflow tract (LVOT) may be a better metric in this setting. In this regard, LVOT velocity time integral (LVOT–VTI), not relying on geometrical assumptions, has been shown to be more reproducible than the calculated stroke volume (i.e., LVOT–VTI * LVOT cross sectional area). Objective To assess the prognostic significance of LVOT–VTI in a contemporary cohort of patients with chronic HF and significant MR. Methods Consecutive patients with chronic HF with reduced (≤40%) or mildly reduced (41–49%) LVEF and moderate–to–severe or severe MR, according to the latest European Society of Cardiology criteria, were selected and followed–up for the endpoint of cardiac death. Results 287 patients were enrolled in the study (74±11 years, 70% men, 46% ischemic etiology, HFrEF 89%, LVEF 30±9%, mean LVOT–VTI 20±5 cm). Most patients showed a NYHA class II (40%) or III (31%) and received beta–blockers (93%), ACE–inhibitors/ARBs or ARNI (77%), and mineralocorticoid receptor antagonists (76%). One hundred and ten patients (39%) had permanent atrial fibrillation and 82 (29%) a cardiac resynchronization therapy device. Over a median follow–up of 33 (16–47) months, 114 patients died, 71 of whom for cardiac cause, and 28 underwent mitral valve repair/replacement. The risk of cardiac death increased proportionally to the decrease of LVOT–VTI (Figure 1, panel A), with an optimal prognostic cut–off of 17 cm (Figure 1, panel B). Reduced LVOT–VTI was associated with higher NYHA class, NT–proBNP concentration, and worse right ventricle systolic function (all p<0.005). At multivariable competing risks regression analysis, a unit decrease of LVOT–VTI (HR 0.87 [95%CI 0.80–0.93], p<0.001), but not of LVEF (p=0.254), was independently associated with a higher risk of cardiac death (Figure 1, panel C). Conclusion Left ventricular forward volume, noninvasively estimated through LVOT–VTI, but not LVEF, predicts the risk of cardiac death in patients with chronic HF and significant MR.