The study aimed to compare the characteristics and outcomes of patients undergoing percutaneous nephrolithotomy (PCNL) in ambulatory surgical centers (ASCs) versus those in a hospital setting. Traditionally, PCNL has been considered an inpatient procedure due to potential risks such as bleeding and infection. However, advancements in surgical techniques and careful patient selection have paved the way for ambulatory PCNL (aPCNL). Researchers analyzed data from 2,107 aPCNL cases performed at two free-standing ASCs and 360 hospital-based PCNL cases between May 2015 and August 2023. Patients with a body mass index (BMI) over 50, severe cardiopulmonary conditions, or previous anesthetic complications were excluded from the ASC. The study found that hospital patients were generally older (average age of 63 vs. 57) and had higher American Society of Anesthesiologists (ASA) scores (3 vs. 2) and BMI (32 vs. 30). Additionally, they had a higher incidence of pre-operative positive urine cultures (37% vs. 18%) and larger stone burdens (38mm vs. 31mm). Complications in the hospital group were more significant, with higher Clavien-Dindo grades (4.7% vs. 1.4%). Conversely, ASC patients were more likely to undergo tubeless procedures (99% vs. 92%), had lower estimated blood loss (34mL vs. 45mL), and required less fluoroscopy time (56s vs. 76s) with shorter operative times (89 minutes vs. 106 minutes). The study concluded that patients selected for hospital PCNL typically have more comorbidities and are at a higher risk for complications, underscoring the importance of patient selection in determining the appropriate setting for PCNL.