Background: Enhanced recovery after surgery programs, also called fast-track protocols, were developed and successfully applied in the last decade for hip and knee reconstruction. Specific fast-track protocols have not yet been applied to ankle prostheses. The aim of the study was to develop and validate an enhanced recovery protocol for total ankle replacement (TAR) evaluating the clinical and radiographic results. We hypothesize that on the basis of well-defined pre- and postoperative characteristics, the current knowledge on ankle replacement, and referring to hip and knee reconstruction, it is possible to identify a "patient type" to be safely eligible to a Fast-Track Protocol with at least comparable results and without increasing the complications risk. Methods: We identified 8 predictive variables that might affect the outcome of TAR. Those variables were the body mass index, the state of anxiety or depression, the functional preoperative status, ankle equinus, the coronal malalignment, the surgical time, the surgical accessory procedures, and the bone quality. These characteristics were evaluated for each patient with almost validated outcome tools attributing a specific score. Based on the score obtained, the patients were divided into 2 groups: the Standard Protocol group (Control Group) and the Fast-Track Protocol group (Study Group). The main difference between treatment of the 2 groups relates to the use of postoperative plaster casts: in the Fast-Track group the cast was removed the first day after surgery and walking was allowed in sports shoes assisted with crutches, whereas in the Standard Protocol group, the cast was removed after 3 weeks. Clinical and radiographic evaluation was performed for all patients preoperatively and postoperatively every 6 months. Results: A total of 163 patients received a score between 1 and 5 and were included in the control group (Standard Protocol); 47 patients received a score of 0 and were allocated to the study group (Fast-Track Protocol). Clinically, except for the preoperative American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scale score, no statistically significant differences were recorded in the multiple comparisons between the 2 groups. No significant differences were found regarding complications. Conclusion: In selected patients, it is possible to apply an enhanced recovery protocol of rehabilitation, focused on immediate weightbearing and mobilization without any plaster or boot. Level of Evidence: Level II, prospective comparative study.