Same-day surgery is an increasingly utilized and cost-effective strategy to manage common surgical conditions. However, many institutions limit ambulatory surgical services to only healthy individuals. There is also a paucity of data on the safety of same-day discharge among high-risk patients. This study aims to determine whether same-day discharge is associated with higher major morbidity and readmission rates compared with overnight stay in high-risk general surgery patients. This is a retrospective cohort using the data from the National Surgical Quality Improvement Program from 2005 to 2017. Patients with an American Society of Anesthesiologists class ≥3 undergoing general surgical procedures amenable to same-day discharge were identified. Primary and secondary outcomes were major morbidity and readmission at 30 d. A multivariable logistic regression model using mixed effects was used to adjust for the effect of same-day discharge. Of 191,050 cases, 137,175 patients (72%) were discharged on the same day. At 30 d, major morbidity was 1.0%, readmission 2.2%, and mortality <0.1%. Adjusted odds ratio of same-day discharge was 0.59 (95% confidence interval 0.54-0.64; P < 0.001) for major morbidity and 0.75 (95% confidence interval 0.71-0.80; P < 0.001) for readmission. Significant risk factors for morbidity and readmission included nonindependent functional status, ascites, renal failure, and disseminated cancer. Major morbidity and readmission rates are low among this large sample of high-risk general surgery patients undergoing common ambulatory procedures. Same-day discharge was not associated with increased adverse events and could be considered in most high-risk patients after uncomplicated surgery. [ABSTRACT FROM AUTHOR]