The purpose of this study was to compare the epidemiologic and demographic profiles and inpatient postoperative complication and economic outcomes of patients undergoing total joint arthroplasty of the hip and knee (TJA) at high-volume centers (HVCs) versus low-volume centers (LVCs) using a large national registry. This retrospective cohort study used data from the National Inpatient Sample from 2006 to the third quarter of 2015. Discharges representing patients aged 40 years or older receiving a primary total hip arthroplasty or total knee arthroplasty were included. Patients were stratified into those undergoing their procedure at HVCs versus LVCs. Epidemiologic, demographic, and inpatient postoperative complications and economic outcomes were comparatively analyzed between groups. A total of 7,694,331 TJAs were conducted at HVCs while 1,044,358 were conducted at LVCs. Patients at LVCs were more likely to be female, be Hispanic, be non-Hispanic Black, and use Medicare and Medicaid than patients at HVCs. Of the 29 Elixhauser comorbidities examined, 14 were markedly higher at LVCs while 11 were markedly higher at HVCs. Patients who underwent TJA at LVCs were more likely to develop cardiac, respiratory, gastrointestinal, genitourinary, hematoma/seroma, wound dehiscence, and postoperative infection complications and were more likely to die during hospitalization. Patients at HVCs were more likely to develop postoperative anemia. Length of stay and total charges were higher at LVCs compared with HVCs. There are notable differences in the demographics, epidemiologic characteristics, and inpatient outcomes of patients undergoing TJA at HVCs versus LVCs. Attention should be directed to identifying and applying the specific resources, processes, and practices that improve outcomes at HVCs while referral practices and centralization efforts should be mindful to not worsen already existing disparities.