Background: Septic arthritis of the shoulder is a rare but devastating condition that may lead to joint destruction. There are few studies and limited outcome data on shoulder arthroplasty for infected native shoulders with end-stage glenohumeral arthritis (GHA).Hence, this study aimed to demonstrate the clinical outcomes of two-stage implantation in reverse shoulder arthroplasty (RSA) using an antibiotic spacer in the first stage for this challenging condition. Methods: We conducted a retrospective study on two-stage implantation in RSA in infected shoulders. Patients were diagnosed with end-stage GHA due to primary shoulder sepsis or infection following non-arthroplasty shoulder surgery. Laboratory data, range of motion (ROM), and functional scores including American Shoulder and Elbow Surgeons score, Constant score, and Disabilities of the Arm, Shoulder and Hand score were assessed prior to spacer placement and at the latest follow-up. Furthermore, intraoperative and postoperative complications were recorded. Results: In this study, 10 patients with a mean age of 54.8 ± 15.8 years (range, 30–77 years) were included. The mean follow-up period was 37.3 ± 9.1 months (range, 25–56 months). All postoperative ROM measurements and functional scores were improved significantly. Although no reinfection was observed, a total of 5 complications including 2 hematomas, 1 intraoperative humeral fracture, 1 humeral stem loosening, and 1 anterior deltoid dysfunction were observed in 4 patients after a follow-up period of at least 2 years after RSA. Conclusions Two-stage implantation in RSA is an effective method for improving the function and controlling the infection in postinfectious end-stage GHA in native shoulders.