<h3>Objective:</h3> We sought to examine contemporary relationships between hospital acute ischemic stroke (AIS) volumes and outcomes. <h3>Background:</h3> Prior research on AIS volume-based patient outcomes demonstrated contradictory results and failed to reflect recent advances in stroke care. <h3>Design/Methods:</h3> We used complete Medicare datasets in a retrospective cohort study employing validated International Classification of Diseases Tenth Revision codes to identify patients admitted with AIS from January 1, 2016 through December 31, 2019. AIS volume was calculated as the total number of AIS admissions per hospital during the study period. We examined hospital characteristics by AIS volume quartile. We performed adjusted logistic regression testing associations of AIS volume with: inpatient mortality, receipt of tissue plasminogen activator (tPA) and endovascular therapy (ET), discharge home and 30-day outpatient visit. We adjusted for sex, age, Charlson comorbidity score, teaching hospital status, socioeconomic status, hospital urban-rural designation, stroke certification status, and ICU and neurologist availability at the hospital. <h3>Results:</h3> There were 952400 AIS admissions among 5084 US hospitals; AIS 4-year volume quartiles were: 1st: 1–8 AIS admissions; 2nd: 9–44; 3rd: 45–237; 4th: 238+. Highest quartile hospitals more often were stroke-certified (49.1% vs 8.7% in lowest quartile, p<0.0001), with ICU bed availability (19.8% vs 4.1%, p<0.0001) and with neurologist expertise (91.1% vs 3%, p<0.0001). For every ten-unit increase in volume, there were higher odds of receiving tPA (OR 1.009, 95% CI 1.008–1.01, p<0.0001) and ET (1.041, 1.037–1.046, p<0.0001), but also higher inpatient mortality (1.004, 1.003–1.005, p<0.0001) and 30-day mortality (1.001, 1.001–1.002, p<0.0001). <h3>Conclusions:</h3> High AIS-volume hospitals have greater utilization of acute stroke interventions, stroke certification and availability of neurologist and ICU care. Despite these advantages, higher AIS volumes were associated with increased inpatient and 30-day mortality. Further research is needed to better understand volume-outcome relationships in AIS to provide effective stroke care and accurately risk-adjust hospital outcomes. <b>Disclosure:</b> Dr. McCarthy has nothing to disclose. Dr. Daniel has nothing to disclose. Dr. Santos has nothing to disclose. Dr. Dhamoon has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Faegre Baker Daniels LLP. Dr. Dhamoon has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Wellstar Health System Inc. Dr. Dhamoon has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Fabiani Cohen & Hall, LLP. Dr. Dhamoon has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Kramer, Dillof, Livingston & Moore. Dr. Dhamoon has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Robins Kaplan. Dr. Dhamoon has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Parker Waichman LLP. Dr. Dhamoon has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Heidell, Pittoni, Murphy & Bach, LLP.