Objective: To examine the incidence and risk factors of in-hospital prosthesis-related complications (PRCs) following total knee arthroplasty (TKA) using a large-scale national database., Methods: A retrospective database analysis was performed based on Nationwide Inpatient Sample (NIS) from 2005-2014. Patients who underwent TKA were included. The recruited cases were divided into two groups according to the occurrence of PRCs. Patient demographics (age, sex, and race), hospital characteristics (type of admission and payer, and bedsize, teaching status, location, and region of hospital), length of stay (LOS), total charges during hospitalization, in-hospital mortality, comorbidities, and perioperative complications were analyzed., Results: A total of 1,227,244 TKAs were captured from the NIS database. There were 8484 cases of in-hospital PRCs after TKA and the overall incidence was 0.69%, with a slight downward trend annually. Periprosthetic joint infection (PJI) was the main category among PRCs (0.20%), followed by mechanical loosening (0.04%), dislocation (0.02%), and periprosthetic fracture (PPF) (0.01%). Patients suffered from in-hospital PRCs were 3 years younger (64 years vs 67 years) and 6.51% more likely to be male (43.60% vs 37.09%) compared to the nonaffected population (P < 0.0001). Additionally, patients experiencing in-hospital PRCs after TKA were 2.11% less likely through elective admission (92.07% vs 94.18%) while 2.34% more likely in teaching hospital (45.53% vs 43.19%) than those without these complications (P < 0.0001). Furthermore, the occurrence of in-hospital PRCs was associated with longer LOS (4 days vs 3 days; P < 0.0001), more total charges ($53,418 vs $41,204, P < 0.0001), and higher in-hospital mortality (0.30% vs 0.07%; P < 0.0001). Multivariate logistic regression was performed to identify independent risk factors of in-hospital PRCs after TKA which included younger age, male, non-elective admission, teaching hospital, deficiency and chronic blood loss anemia, coagulopathy, congestive heart failure, depression, diabetes with chronic complications, fluid and electrolyte disorders, pulmonary circulation disorders, metastatic cancer, and weight loss. Besides, in-hospital PRCs after TKA were associated with secondary osteoarthritis, inflammatory arthritis, prior knee arthroscopy, acute renal failure, acute myocardial infarction, deep vein thrombosis, sepsis, transfusion, and wound dehiscence., Conclusion: It is beneficial to study the risk factors of in-hospital PRCs after TKA to ensure the appropriate management and optimize consequences although a relatively low incidence was identified., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)