Background The clinical significance of mitral annular calcification (MAC) in patients undergoing mitral transcatheter edge-to-edge repair is not well understood. There is limited evidence regarding the feasibility, durability of repair, and the prognostic value of MAC in this population. We sought to examine the prognostic value of MAC, its severity, and its impact on procedural success and durability of mitral transcatheter edge-to-edge repair. Methods and Results We reviewed the records of 280 patients with moderate-severe or severe mitral regurgitation who underwent mitral transcatheter edge-to-edge repair with MitraClip from March 2014 to March 2022. The primary end point was cumulative survival at 1 year. Independent factors associated with the primary end point were identified using multivariable Cox regression. Among 280 patients included in the final analysis, 249 had none/mild MAC, and 31 had moderate/severe MAC. Median follow-up was 23.1 months (interquartile range: 11.1-40.4). Procedural success was comparable in the MAC and non-MAC groups (92.6% versus 91.4%, =0.79) with similar rates of residual mitral regurgitation ≤2 at 1 year (86.7% versus 93.2%, =0.55). Moderate/severe MAC was associated with less improvement in New York Heart Association III/IV at 30 days when compared with none/mild MAC (45.8% versus 14.3%, =0.001). The moderate/severe MAC group had lower cumulative 1-year survival (56.8% versus 80.0%, hazard ratio [HR], 1.98 [95% CI, 1.27-3.10], =0.002). Moderate/severe MAC and Society of Thoracic Surgeons predicted risk of mortality for mitral valve repair were independently associated with the primary end point (HR, 2.20 [1.10-4.41], =0.02; and HR, 1.014 [1.006-1.078], =0.02, respectively). Conclusions Mitral TEER is a safe and feasible intervention in selected patients with significant MAC and associated with similar mitral regurgitation reduction at 1 year compared with patients with none/mild MAC. Patients with moderate/severe MAC had a high 1-year mortality and less improvement in their symptoms after TEER.