Background: Total ankle arthroplasty (TAA) is a preferred surgical option for end-stage ankle osteoarthritis; however, it is a demanding procedure with a higher historical rate of revision compared with ankle fusion. Patient-specific instrumentation (PSI) has been introduced to optimize prosthesis alignment and theoretically overall improve TAA outcomes. The goal of this study is to report on the experience and surgical outcomes of one implant with specific evaluation of the accuracy and reproducibility of the system with respect to prosthesis alignment and prediction of implant size. Methods: A retrospective, multicentered study involving 4 foot and ankle fellowship–trained orthopaedic surgeon’s patients undergoing TAA between January 1, 2015, and December 31, 2018, using the PROPHECY PSI system. Results: 80 TAA procedures were performed. On average the postoperative tibial component alignment was 89.9 (range, 86.1-96.5) degrees in the coronal plane, with a mean sagittal alignment of 88.1 (range, 81.3-96.7) degrees. The mean deviation from neutral sagittal alignment improved from 4.9 ± 3.9 degrees preoperatively to 2.7 ± 1.7 degrees postoperatively, whereas the mean coronal alignment improved from 3.3 ± 2.5 degrees to 1.3 ± 1.1 degrees. The PSI software correctly determined the tibial implant size in 70 patients (89%). Prediction of talar implant sizing was less accurate than the tibial component, with 56 patients (71%) using the predicted sized implant. The overall implant survival at a mean follow-up of 45 months (range, 27-76) was 97.5%. Conclusion: We found that this PSI system accurately and reliably assisted in implant total ankle prosthesis positioning within a clinically acceptable margin and without significant outliers. Prediction of implant size was not as accurate as component orientation. Level of Evidence: Level III, retrospective study.