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Major revision is associated with less satisfactory outcomes, substantial complications, and added cost. Data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) were analyzed to identify factors associated with major aseptic revision (MAR) of primary total knee replacement (TKR).The cumulative percent major aseptic revision rate following all primary TKRs performed in Australia from September 1, 1999, to December 31, 2015, was assessed. Kaplan-Meier estimates of survivorship were utilized to describe the time to first revision. Hazard ratios (HRs) from Cox proportional hazard models, adjusted for age and sex, were utilized to compare revision rates.There were 5,973 MARs recorded from the total cohort of 478,081 primary TKRs. The cumulative percent MAR at 15 years was 3.0% (95% confidence interval [CI], 2.8% to 3.2%). Fixed bearings had a significantly lower rate of MAR at 15 years: 2.7% (95% CI, 2.4% to 2.9%) compared with 4.1% (95% CI, 3.8% to 4.5%) for mobile bearings (HR, 1.77 [95% CI, 1.68 to 1.86]; p < 0.001). Age had a significant effect on MAR rates, with a cumulative percent revision at 15 years for patients <55 years old of 7.8% (95% CI, 6.5% to 9.2%) compared with 1.0% for those ≥75 years old (95% CI, 0.8% to 1.1%; p < 0.001). Minimally stabilized TKR had a lower rate of MAR compared with posterior-stabilized TKR after 2 years (HR, 0.83 [95% CI, 0.77 to 0.90]; p < 0.001). Cementless fixation had a higher rate of revision than cemented or hybrid fixation. There was a higher rate of MAR with non-navigated compared with computer navigated TKR (HR, 1.32 [95% CI, 1.21 to 1.44], p < 0.001). The tibial component was revised more commonly than the femoral component.Younger age, posterior stabilization, cementless fixation, a mobile bearing, and non-navigation were risk factors for higher rates of MAR following TKR.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.