Prosthetic reconstruction after resecting giant cell tumor of bone (GCTB) of the distal radius has been proposed. However, this is generally associated with various complications. To improve the functional outcomes, we designed a three-dimensional (3D)-printed uncemented endoprosthesis. Meanwhile, using finite-element analysis and clinical observation, an optimization strategy was explored.We retrospectively analyzed patients with Campanacci III or recurrent GCTB of the distal radius who underwent 3D-printed uncemented endoprosthesis reconstruction. Clinically, according to the different palmar tilts of the endoprosthesis, patients were divided into the biological angle (BA) group and the zero-degree (ZD) group. We recorded and evaluated the differences in functional outcomes and complications between the two groups. Biomechanically, four 3D finite-element models (normal and customized endoprostheses with three different implemented palmar tilts) were developed.We analyzed 22 patients (12 males and 10 females). The median follow-up period was 60 (range, 19-82) months. Of the 22 patients, 11 patients were included in the BA group and the remaining 11 patients were in the ZD group. Both groups showed no significant differences in the range of motion, Mayo score, and disabilities of the arm, shoulder, and hand scores postoperatively. The subluxation rate was significantly lower in the ZD group than in the BA group. The biomechanical results showed similar stress and displacement distribution patterns in the normal and prosthetic reconstruction models. Additionally, the endoprosthesis with 0° palmar tilt showed better biomechanical performance.3D-printed uncemented endoprosthesis provides acceptable midterm outcomes in patients undergoing distal radius reconstruction. Optimizing the design by decreasing the palmar tilt may be beneficial for decreasing the risk of wrist joint subluxation.© 2023 Wiley Periodicals LLC.