Background <p>Significant mitral regurgitation (MR), is associated with unfavorable perioperative and periprocedural outcomes in patients undergoing cardiac and noncardiac interventions. This may be especially important in left atrial procedures. However, information regarding its impact on percutaneous left atrial appendage closure (LAAC) procedures is scarce.</p> Methods <p>We utilized the National Inpatient Sample (NIS) database to identify patients who underwent percutaneous LAAC and had an MR diagnosis between the years 2016 and 2021 in the US, using ICD-10 codes. Clinical and sociodemographic data, in-hospital procedures and outcomes were collected. Baseline characteristics and outcomes were compared between patients with and without MR. Multivariable logistic regression models were used to identify predictors of in-hospital complications.</p> Results <p>An estimated total of 123,785 patients underwent percutaneous LAAC between 2016 and 2021 in the US. Of them, 7,325 (5.9%) patients had an MR diagnosis. Compared to non-MR patients, MR patients were older and had higher CHA₂DS₂-VASc and ATRIA bleeding scores. MR patients had a higher rate of total complications (6.1% vs. 5.3%, <i>p</i> = 0.004), driven mainly by acute kidney injury (AKI, 3.3% vs. 2.0%, <i>p</i> &lt; 0.001). Multivariable analysis confirmed MR as an independent predictor for AKI (OR = 1.38, 95% CI:1.02–1.88, <i>p</i> = 0.039), but not for total complications. In-hospital mortality was low, with no significant difference between patients with and without MR.</p> Conclusion <p>In patients undergoing percutaneous LAAC, MR was independently associated with an increased risk for AKI, but not for cardiac and vascular complications or in-hospital mortality in a US nationwide, all-comer registry.</p> Graphical abstract <p></p>