OBJECTIVES This study sought to evaluate the impact of moderate to severe aortic insufficiency (AI) on outcomes in patients with continuous flow left ventricular assist devices (CF-LVADs). BACKGROUND Development of worsening Al is a common complication of prolonged CF-LVAD support and portends poor prognosis in single-center studies. Predictors of worsening Al and its impact on clinical outcomes have not been examined in a large cohort. METHODS We conducted a retrospective analysis of patients with CF-LVAD in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) study. Development of significant AI was defined as the first instance of at least moderate AI Primary outcomes of interest were survival after development of significant AI and time to adverse events, including device complications and rehospitatizations. RESULTS Among 10,603 eligible patients, 1,399 patients on CF-LVAD support developed moderate to severe AI. Prevalence of significant AI progressively increased over time. Predictors of worsening AI included older age, female sex, smaller body mass index, mild pre-implantation AI, and destination therapy strategy. Moderate to severe AI was associated with significantly higher left ventricular end-diastolic diameter, reduced cardiac output, and higher levels of brain natriuretic peptide. Significant AI was associated with higher rates of rehospitalization (32.1% vs. 26.6%, respectively, at 2 years; p 0.015) and mortality (77.2% vs. 71.4%, respectively, at 2 years; p 0.005), conditional upon survival to 1 year. CONCLUSIONS Development of moderate to severe AI has a negative impact on hemodynamics, hospitalizations, and survival on CF-LVAD support. Pre- and post-implantation management strategies should be developed to prevent and treat this complication. (C) 2018 by the American College of Cardiology Foundation.