Background: As the popularity of total ankle arthroplasty (TAA) increases and indications expand, surgeons require a better understanding of which patient factors are associated with implant failure. In this study, we aimed to use a large total ankle database to identify independent risk factors for implant failure at mid- to long-term follow-up. Methods: A prospectively collected database was used to identify all patients who underwent primary TAA with a minimum 5 years’ follow-up. The primary outcome was revision, defined as removal of one or both metal components; failures due to infection were excluded. Patient and clinical factors analyzed included age, sex, body mass index (BMI), smoking status, presence of diabetes, indication for TAA, implant, tourniquet time, and presence of ipsilateral hindfoot fusion. Preoperative coronal deformity and sagittal talar translation were assessed, as were postoperative coronal and sagittal tibial component alignment. Univariable and multivariable analyses were performed to identify predictors of implant failure. After excluding 5 ankles that failed because of deep infection, 533 ankles with a mean 7 (range, 5-11) years of follow-up met the inclusion criteria. Four implants were used: INBONE I, INBONE II, STAR, and Salto-Talaris. Results: Thirty-four ankles (6.4%) were revised or removed a mean 4 (range, 1-9) years postoperatively. The only independent predictors of failure were the INBONE I prosthesis and ipsilateral hindfoot fusion ( P = .006 and P = .023, respectively). Conclusions: This is among the largest studies to analyze the relationship between TAA failure rates and multiple different patient, operative, and radiographic factors. Of note, age, BMI, and amount of deformity were not associated with higher failure rates. Only patients with ipsilateral hindfoot fusion or who received the INBONE I prosthesis were at significantly higher risk of implant failure. Level of Evidence: Level III, retrospective cohort study.