INTRODUCTION Guideline-directed medical therapy (GDMT), based on the combination of beta blockers (BB), renin-angiotensin system inhibitors (RAS-I), and mineralocorticoid-receptor antagonists (MRA), is known to have a major impact on the outcome of the patients with heart failure with reduced ejection fraction (HFrEF). Although GDMT is recommended prior to M-TEER, not all patients tolerate it. We studied the association of GDMT prescription with survival in HFrEF patients undergoing mitral valve transcatheter edge-to-edge repair (M-TEER) for secondary mitral regurgitation (SMR). METHODS AND RESULTS EuroSMR, a European multicenter registry, included SMR patients with left ventricular ejection fraction of less than fifty percent. The outcome was 2-year all-cause mortality. Of 1344 patients, BB, RAS-I, and MRA were prescribed in 1169 (87%), 1012 (75%), and 765 (57%) patients at the time of M-TEER, respectively. Triple GDMT prescription was associated with a lower 2-year all-cause mortality compared to non-triple GDMT (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.60-0.91). The association persisted in patients with glomerular filtration rate of <30ml/min, ischemic etiology, or right ventricular dysfunction. Further, a positive impact of triple GDMT prescription on survival was observed in patients with residual MR of ≥2+ (HR, 0.62; 95% CI, 0.44-0.86), but not in patients with residual MR of ≤1+ (HR, 0.83; 95% CI, 0.64-1.08). CONCLUSION Triple GDMT prescription is associated with higher 2-year survival after M-TEER in HFrEF patients with SMR. This association was consistent also in patients with major comorbidities or non-optimal results after M-TEER.