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Background: Coronavirus disease 2019 (COVID-19) changed the practice of medicine in America. During the March 2020 lockdown, elective cases were canceled to conserve hospital beds/resources resulting in financial losses for health systems and delayed surgical care. Ambulatory percutaneous nephrolithotomy (aPCNL) has been shown to be safe and could be a strategy to ensure patients receive care that has been delayed, conserve hospital resources, and maximize cost-effectiveness. We aimed to compare the safety and cost-effectiveness of patients undergoing aPCNL against standard PCNL (sPCNL). Materials and Methods: Ninty-eight patients underwent PCNL at Indiana University Methodist Hospital, a tertiary referral center, by three expert surgeons from January 2020 to September 2020. The primary outcome of the study was to compare the 30-day rates of emergency department (ED) visits, readmissions, and complications between sPCNL and aPCNL. Secondary outcomes included cost analysis and stone-free rates (SFRs). Propensity score matching was performed to ensure the groups were balanced. Statistical analyses were performed using SAS 9.4 using independent t-tests for continuous variables and chi-square analyses for categorical variables. Results: Ninety-eight patients underwent PCNL during the study period (sPCNL = 75 and aPCNL = 23). After propensity score matching, 42 patients were available for comparison (sPCNL = 19 and aPCNL = 23). We found no difference in 30-day ED visits, readmissions, or complications between the two groups. aPCNL resulted in cost savings of $5327 ± 442 per case. SFRs were higher for aPCNL compared with sPCNL. Conclusions: aPCNL appears safe to perform and does not have a higher rate of ED visits or readmissions compared with sPCNL. aPCNL may also be cost-effective compared with sPCNL. [ABSTRACT FROM AUTHOR]