Background: Peri-implant osteolysis is one of the major complications related to total ankle replacement. The aim of this study was to investigate the short- to midterm incidence of peri-implant osteolysis using computed tomography (CT) as imaging method for the Trabecular Metal Total Ankle (TMTA) implant representing a novel total ankle replacement (TAR) implant design regarding material and surgical technique. Methods: In total, 104 consecutive patients who had a primary TMTA replacement between March 2013 and October 2017 were included in the study. The radiographic evaluation included weightbearing anteroposterior and lateral views at baseline and after 3, 6, and every 12 months postoperatively. A helical CT was undertaken preoperatively and of the 80 patients available to follow up at least 12 months postoperatively, with average time interval between the TAR operation and the latest CT of 39 (range, 12-85) months. Results: Eight of 80 patients had altogether 11 osteolytic lesions around the components on CT images. Seven lesions were found in tibia, 3 in talus, and 1 in distal fibula. Four of the tibial lesions were situated in the medial malleolus and were not in contact with the prosthesis component. The sizes of the osteolytic lesions ranged between 7 and 20 mm, and the average volume of the lesions was 689 mm3. Conclusion: We conclude that the risk of peri-implant osteolysis with the TMTA implant is minimal in short to midterm. The anatomic configuration, unique material, and surgical technique may all contribute to the TMTA implant having a low rate of peri-implant osteolysis. Level of Evidence: Level IV, case series.