Background: Total shoulder arthroplasty for end-stage glenohumeral arthritis with severe glenoid bone loss poses a unique challenge for shoulder surgeons. Current surgical solutions are limited and associated with high complication rates. We hypothesized that a custom-made computer-aided design-computeraided manufacturing (CAD-CAM) total shoulder replacement (TSR; Stanmore Implants Worldwide, Elstree, UK) resembling a total hip prosthesis could offer a reliable alternative for this challenging subset of patients. Methods: Thirty-seven patients with rotator cuff-deficient end-stage glenohumeral arthritis and severe glenoid bone loss (assessed as not amenable to treatment with standard anatomic or reverse total shoulder implants) were treated with the CAD-CAM TSR between 2006 and 2013. Clinical data were collected prospectively and analyzed at a mean follow-up of 5 years. Results: Postoperatively, the pain level with activity decreased from 9.2 +/- 1.7 to 2.4 +/- 2.9 (P <.001). The Oxford Shoulder Score improved from 11 +/- 8 points to 27 +/- 11 points (P <.001), and the Subjective Shoulder Value (on a 0%-100% scale) improved from 23% +/- 14% to 60% +/- 24% (P <.001). Active forward elevation improved from 39 degrees +/- 23 degrees to 63 degrees +/- 38 degrees (P <.001), and external rotation improved from 6 degrees +/- 16 degrees to 15 degrees +/- 17 degrees (P =.001). Component revision was required in 6 of 37 patients (16%) (glenoid loosening in 1, humeral stem loosening in 3, periprosthetic fracture in 1, and prosthesis dislocation in 1). Conclusion: The CAD-CAM TSR offers a reliable alternative for the treatment of end-stage glenohumeral arthritis with severe glenoid deficiency not amenable to standard anatomic or reverse total shoulder implants, with maintenance of significant pain relief and clinical-functional improvement at 5-year postoperative follow-up. (C) 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.