Background: Anatomic total shoulder arthroplasty with a nonspherical humeral head and inlay glenoid replacement has been introduced in the past; however, clinical evidence remains limited. We hypothesized that patients with advanced glenohumeral arthritis demonstrate significant improvements in pain and function. Methods: Prospective patient-reported outcomes (PROs) included the American Shoulder and Elbow Surgeons score, a pain visual analog scale, and satisfaction. Range of motion was compared to the preoperative status. A sensitivity analysis examined responder rates and compared them to literature thresholds using the minimal clinically important difference and substantial clinical benefit. The preoperative glenoid morphology was determined using the Walsh classification. Zone-specific periprosthetic radiolucent lines were quantified at the last follow-up. Results: Thirty-nine shoulders in 36 patients (3 bilateral) with a mean age of 65.9 years (26 males, 13 females) and a mean follow-up of 41.0 months were included. Ninety-three percent had grade III osteoarthritis, and 7% grade II. The glenoid Walsh classification included A1 (25%), A2 (25%), B1 (22%), B2 (25%), and C (3%). All PROs improved significantly (P < .001) with a mean American Shoulder and Elbow Surgeons score from 30.4 to 77.1, a pain visual analog scale from 8.1 to 1.5, and excellent (9.1/10) patient satisfaction. PRO-related responder rates for minimal clinically important difference and substantial clinical benefit were ≥85%. Forward elevation improved from 107° to 155°, and external rotation from 22° to 51°. One intraoperative glenoid rim fracture led to advanced radiolucency; no other clinically relevant lucency was observed. Conclusion: Treatment with inlay total shoulder arthroplasty demonstrated significant functional improvement, excellent pain relief, and patient satisfaction in patients with advanced shoulder arthritis and various glenoid morphology types. Our initial results provide further support for this new option in primary shoulder replacement.