Background Little is known about the impact of transcatheter mitral valve edge‐to‐edge repair on changes in left ventricular ejection fraction (LVEF) and the effect of an acute reduction in LVEF on prognosis. We aimed to assess changes in LVEF after transcatheter mitral valve edge‐to‐edge repair for both primary and secondary mitral regurgitation (PMR and SMR, respectively), identify rates and predictors of LVEF reduction, and estimate its impact on prognosis. Methods and Results In this international multicenter registry, patients with both PMR and SMR undergoing transcatheter mitral valve edge‐to‐edge repair were included. We assessed rates of acute LVEF reduction (LVEFR), defined as an acute relative decrease of >15% in LVEF, its impact on all‐cause mortality, major adverse cardiac event (composite end point of all‐cause death, mitral valve surgery, and residual mitral regurgitation grade ≥2), and LVEF at 12 months, as well as predictors for LVEFR. Of 2534 patients included (727 with PMR, and 1807 with SMR), 469 (18.5%) developed LVEFR. Patients with PMR were older (79.0±9.2 versus 71.8±8.9 years; P <0.001) and had higher mean LVEF (54.8±14.0% versus 32.7±10.4%; P <0.001) at baseline. After 6 to 12 months (median, 9.9 months; interquartile range, 7.8–11.9 months), LVEF was significantly lower in patients with PMR (53.0% versus 56.0%; P <0.001) but not in patients with SMR. The 1‐year mortality was higher in patients with PMR with LVEFR (16.9% versus 9.7%; P <0.001) but not in those with SMR ( P =0.236). LVEF at baseline (odds ratio, 1.03 [95% CI, 1.01–1.05]; P =0.002) was predictive of LVEFR for patients with PMR, but not those with SMR ( P =0.092). Conclusions Reduction in LVEF is not uncommon after transcatheter mitral valve edge‐to‐edge repair and is correlated with worsened prognosis in patients with PMR but not patients with SMR. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05311163.