Background: There is much debate regarding the best outcome tool for use in foot and ankle surgery, specifically in patients with ankle arthritis. The Ankle Osteoarthritis Scale (AOS) is a validated, disease-specific score. The goals of this study were to investigate the clinical performance of the AOS and to determine a minimal clinically important difference (MCID) for it, using a large cohort of 238 patients undergoing surgery for end-stage ankle arthritis. Methods: Patients treated with total ankle arthroplasty or ankle arthrodesis were prospectively followed for a minimum of two years at a single site. Data on demographics, comorbidities, AOS score, Short Form-36 results, and the relationship between expectations and satisfaction were collected at baseline (preoperatively), at six and twelve months, and then yearly thereafter. A linear regression analysis examined the variables affecting the change in AOS scores between baseline and the two-year follow-up. An MCID in the AOS change score was then determined by employing an anchor question, which asked patients to rate their relief from symptoms after surgery. Results: Surgical treatment of end-stage ankle arthritis resulted in a mean improvement (and standard deviation) of 31.2 +/- 22.7 points in the AOS score two years after surgery. The MCID of the AOS change score was a mean of 28.0 +/- 17.9 points. The change in AOS score was significantly affected by the preoperative AOS score, smoking, back pain, and age. Conclusions: Patients undergoing arthroplasty or arthrodesis for end-stage ankle arthritis experienced a mean improvement in AOS score that was greater than the estimated MCID (31.2 versus 28.0 points).