There are limited data about the role of cardiac resynchronization therapy (CRT) in adults with congenital heart disease (CHD) and heart failure with reduced ejection fraction (HFrEF). (i) Assess the relationship between CRT and clinical outcomes (all-cause mortality and cardiovascular events). (ii) Assess temporal changes in clinical indices of disease severity (NYHA class, peak oxygen consumption, NT-proBNP, and LVEF) post-CRT. Retrospective study of adults with CHD, biventricular circulation and systemic LV and HFrEF who received CRT at Mayo Clinic (2003-203). Clinical indices of disease severity were assessed pre-CRT and 1-year post-CRT. We defined a CRT responder as a patient with absolute increase in LVEF ≥10% and improvement in NYHA class by ≥1 unit post-CRT. Intensity of HF therapy was assessed using the guideline-directed medical therapy (GDMT) score. Of 327 CHD patients with HFrEF, 105 (32%) received CRT (age 51±15 years, 68% males). CRT was associated with 24% decrease in mortality (adjusted hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.51, 0.97), and 21% decrease in cardiovascular events (adjusted HR 0.79, 95%CI 0.63, 0.94). Of the 105 patients, 71 (68%) were CRT responders. Higher GDMT score was associated with greater odds of CRT response (adjusted odds ratio 1.28, 95% CI 1.04, 1.47). CRT responders had greater temporal improvement in NYHA class, peak oxygen consumption, NT-proBNP levels, and lower risk of cardiovascular events (unadjusted HR 0.73, 95% CI 0.47, 0.99). These data highlight the clinical benefits of CRT and GDMT for management of HFrEF in CHD and support the use of these therapies in this population.