Background— Safety data on percutaneous left atrial appendage closure arises from centers with considerable expertise in the procedure or from clinical trial, which might not be reproducible in clinical practice. We sought to estimate the frequency and predictors of adverse outcomes and costs of percutaneous left atrial appendage closure procedure in the US. Methods and Results— The data were obtained from the Nationwide Inpatient Sample from the years 2006 to 2010. The Nationwide Inpatient Sample is the largest all-payer inpatient data set in the US. Complications were calculated using patient safety indicators and International Classification of Diseases -Ninth Revision, Clinical Modification codes. Annual hospital volume was calculated using unique hospital identifiers. Weights provided by the Nationwide Inpatient Sample were used to generate national estimates. A total of 268 (weighted=1288) procedures were analyzed. The overall composite rate of mortality or any adverse event was 24.3% (65), with 3.4% patients required open cardiac surgery after procedure. Average length of stay was 4.61±1.05 days and cost of care was 26 024±34 651. Annual hospital procedural volume was significantly associated with reduced complications and mortality (every unit increase: odds ratio, 0.89; 95% confidence interval, 0.85–0.94; P <0.001), decrease in length of stay (every unit increase: hazard ratio, 0.95; 95% confidence interval, 0.92–0.98; P <0.001) and cost of care (every unit increase: hazard ratio, 0.96; 95% confidence interval, 0.93–0.98; P <0.001). Conclusions— Our study demonstrates that the frequency of inhospital adverse outcomes associated with percutaneous left atrial appendage closure is higher in the real-world population than in clinical trials. We also demonstrate that higher annual hospital volume is associated with safer procedures, with lower length of stay and cost.