BACKGROUND: Total ankle arthroplasty has shown durable improvements in patient-reported outcomes. However, the impact of common comorbidities and patient factors has not been fully characterized. The purpose of this study was to identify patient comorbidities and characteristics that impact outcomes after total ankle arthroplasty. METHODS: Patients who underwent a total ankle arthroplasty between January 2007 and December 2016 were enrolled into a prospective study at a single academic center. Patients completed outcome measures before the surgical procedure and at the time of follow-up: a visual analog scale (VAS) for pain, the 36-item Short Form Survey (SF-36), and the Short Musculoskeletal Function Assessment (SMFA). Patient and operative factors, along with prevalent preoperative comorbidities, were analyzed for association with preoperative to postoperative changes in 1 to 2-year and minimum 5-year outcomes. Comorbidities that met a significance threshold of p < 0.05 in adjusted analyses were incorporated into multivariable outcome models. RESULTS: A total of 668 patients with a mean 1 to 2-year follow-up (and standard deviation) of 1.6 ± 0.5 years (range, 10 months to 2 years and 2 months) were included. Patients' pain and function significantly improved across all outcomes (p < 0.05). However, depression, staged bilateral ankle arthroplasty, increased length of stay, a prior surgical procedure, increased American Society of Anesthesiologists (ASA) score, and particular implant types were associated with significantly smaller improvements in at least 1 patient-reported outcome after total ankle arthroplasty in the 1 to 2-year follow-up, although the effects were relatively small. At a minimum 5-year follow-up, smoking, depression, implant type, and staged bilateral ankle arthroplasty were associated with worse outcomes, and a prior surgical procedure, a simultaneous bilateral surgical procedure, and obesity were associated with improved outcomes. CONCLUSIONS: Patients who underwent total ankle arthroplasty had significant improvement in patient-reported outcomes, although several factors were associated with a small, but significant, negative impact on improvement, including depression, increased ASA score, current smoking, increased length of stay, a prior surgical procedure, and staged bilateral total ankle arthroplasty. Current smoking, obesity, and depression are potentially modifiable risk factors that could be improved prior to total ankle arthroplasty. Patients with these characteristics should be counseled on their risk of limited improvement in ankle pain and disability after total ankle arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.