Background:The prognostic impact and optimal treatment of left ventricular systolic dysfunction in patients with moderate aortic regurgitation (AR) remain unknown. We aimed to assess the prognostic value of left ventricular ejection fraction (LVEF) in patients with moderate AR and explore the potential benefits of aortic valve intervention (AVI).Methods:In total, 1,211 consecutive patients with moderate AR (jet width, 25–64% of LV outflow tract; vena contracta, 0.3–0.6 cm; regurgitant volume, 30–59 mL/beat; regurgitant fraction, 30–49%; effective regurgitation orifice, 0.10–0.29 cm2) prospectively registered between April and June 2018 at 46 academic hospitals were included. The primary outcome was a composite of death or hospitalization for heart failure (HHF). The optimal LVEF threshold for predicting the primary outcome was determined through the penalized spline shape and maximally selected rank statistics.Results:During the 2-year follow-up, 125 deaths or HHF occurred. In the penalized splines, the relative hazard of death or HHF monotonically increased with decreasing LVEF. In the multivariate analysis, LVEF ≤55% was identified as the best threshold for independently predicting death or HHF under medical treatment (adjusted hazard ratio [HR]: 2.18; 95% confidence interval [CI] 1.38–3.42; P = 0.001), with substantial incremental values (integrated discrimination improvement index = 0.018, P = 0.030; net reclassification improvement index = 0.225, P = 0.006; likelihood ratio test P < 0.001). Among patients with LVEF 35–55%, AVI within 6 months of diagnosis was associated with a reduced risk of death or HHF compared with medical treatment alone (adjusted HR: 0.15; 95% CI: 0.04–0.50; P = 0.002), whereas this benefit was markedly attenuated when LVEF was ≤35% (adjusted HR: 0.65; 95% CI: 0.21–1.97; P = 0.441, P-interaction = 0.010) or >55% (adjusted HR: 0.40; 95% CI: 0.14–1.15; P = 0.089, P-interaction = 0.723).Conclusions:LVEF is an independent and incremental prognostic factor in patients with moderate AR, with LVEF ≤55% being a robust marker of poor prognosis. Patients with LVEF 35–55% may benefit from early surgical correction of moderate AR. Further studies are warranted to validate our findings in a randomized setting.Registration:China Valvular Heart Disease Study (China-VHD study, NCT03484806); clinicaltrials.gov/ct2/show/NCT03484806.