Guideline-directed medical therapy (GDMT) is recommended prior to mitral valve transcatheter edge-to-edge repair (MTEER) in patients with heart failure (HF) and severe functional mitral regurgitation (FMR). Whether MTEER is being performed on the background of optimal GDMT in clinical practice is unknown. Patients with left ventricular ejection fraction (LVEF) < 50% who underwent MTEER for FMR from July 23, 2019 to March 31, 2022 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry were identified. Pre-procedure GDMT utilization was assessed. Cox proportional hazards models were constructed to evaluate associations between pre-MTEER therapy (no/single, double, or triple therapy) and risk of one-year mortality or HF hospitalization (HFH). Among 4,199 patients across 449 sites, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitor were used in 85.1%, 44.4%, 28.6%, and 19.9% prior to MTEER, respectively. Triple therapy was prescribed for 19.2%, double therapy for 38.2%, single therapy for 36.0%, and 6.5% were on no GDMT. Significant center-level variation in the proportion of patients on pre-intervention triple therapy was observed (0-61%; adjusted median odds ratio 1.48 [95% confidence interval (CI) 1.25-3.88]; P < 0.001). In patients eligible for one-year follow-up (n = 2,014; 341 sites), the composite rate of one-year mortality or HFH was lowest in patients prescribed triple therapy (23.1%) compared with double (24.8%), single (35.7%), and no (41.1%) therapy (P < 0.01 comparing across groups). Associations persisted after accounting for relevant clinical characteristics, with lower risk in patients prescribed triple therapy (adjusted hazard ratio [aHR] 0.73, 95% CI 0.55-0.97) and double therapy (aHR 0.69, 95% CI 0.56-0.86) prior to MTEER compared with no/single therapy. Under one-fifth of patients with LVEF <50% who underwent MTEER for FMR in this US nationwide registry were prescribed comprehensive GDMT, with substantial variation across sites. Compared with no/single therapy, triple and double therapy prior to MTEER were independently associated with reduced risk of mortality or HFH one year after intervention.