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The present study was designed to clarify which underlying indications can be currently considered the main reasons for failure after total knee arthroplasty as a function of time.We conducted a retrospective study that included all first revisions of total knee replacements during 2005 to 2010 at two high-volume arthroplasty centers. A revision was defined as the replacement of at least one prosthetic component. In the descriptive analysis, polyethylene wear, aseptic loosening, periprosthetic infection, malalignment, instability, arthrofibrosis, extensor mechanism deficiency, periprosthetic fracture, and retropatellar arthritis were given as the failure mechanism associated with an early, intermediate, or late time interval (less than one year, one to three years, and more than three years, respectively) after the index total knee arthroplasty.Three hundred and fifty-eight revision total knee arthroplasties were included. Of those revisions, 19.8% were performed within the first year after the index arthroplasty. The most common indications for revision, besides aseptic loosening (21.8%), were instability (21.8%), malalignment (20.7%), and periprosthetic infection (14.5%). Revisions due to polyethylene wear (7%) rarely occurred. In the early failure group, the primary causes of revision were periprosthetic infection (26.8%) and instability (23.9%). In the intermediate group, instability (23.3%) and malalignment (29.4%) required revision surgery, whereas late failure mechanisms were aseptic loosening (34.7%), instability (18.5%), and polyethylene wear (18.5%).Aseptic loosening, instability, malalignment, and periprosthetic infection continue to be the primary failure mechanisms leading to revision surgery. Contrary to previous literature, the results in the present study showed a substantial reduction in implant-associated revisions such as those due to polyethylene wear. Failure mechanisms that occur persistently early and in the intermediate term, such as periprosthetic infection, instability, and malalignment, remain common causes of revision surgery.Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.