Objectives We sought to evaluate differences in perioperative baseline characteristics, operative efficiency, and 30-day safety events for patients undergoing standalone minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF) in a hospital versus an ambulatory surgery center (ASC). Methods Patients were retrospectively identified and sequentially enrolled from the office records of a single, community neurosurgeon. Records for the first 50 qualifying patients in the hospital and ASC cohorts were retrieved. Variables collected included: baseline demographic and health status, operative safety (intra-op complications) and efficiency (operative time, fluoroscopy time, etc.), and 30-day post-operative safety (emergency room visits, re-admission, and re-operation). Results At baseline, hospital and ASC patients were equivalent in gender distribution, BMI, and pre-operative narcotic use. Statistically significant differences were found in age and comorbidity burden (ASA status and Charleson Comorbidity Index); p < 0.0001, p = 0.0039, and p < 0.001 respectively. The only significant difference in construct type between hospital and ASC patients was the proportion of one- versus two-level fusions; all two-level fusions were performed in the hospital group. There were no differences in operative time, need for transfusions, or iatrogenic complications. There were also no differences between the groups in 30-day events of ER visits, re-admission, re-operation, or post-operative narcotic refill use. The length of stay was significantly different between the ASC and hospital settings (p < 0.0001). Conclusions As expected, ASC patients were younger and relatively healthier compared to their hospital counterparts. Thirty-day safety events of ER visits, re-admission, re-operation, and narcotic refill utilization were representative of population norms. Patients with standalone, expandable MIS-TLIF underwent efficient operative procedures and experienced minimal 30-day complications independent of their operative status. ASC patients had the added benefit of significantly reduced length of stay over their hospital counterparts. Given the equivalency of the 30-day post-operative course for both patient cohorts, a substantial reduction in economic burden is likely for the ASC patients.