Glenoid bone loss from an infiltrating intramuscular lipoma causing erosive changes is a rare occurrence. A 71-year-old woman with symptomatic rotator cuff arthropathy in the setting of an intramuscular infiltrating lipoma and secondary glenoid bone loss was treated with single-stage tumor excision and reverse total shoulder arthroplasty (rTSA) using an injectable, hard self-setting calcium phosphate as structural bone graft substitute. The patient demonstrated excellent clinical and radiographic outcomes at 2-year follow-up. Infiltrating lipomas resulting in functional rotator cuff arthropathy and erosive osseous glenoid changes are exceedingly rare, yet significant glenoid bony defects present a challenge in the setting of shoulder arthroplasty. This report describes the use of structural bone graft substitute for the management of a glenoid bone defect from a rare case of an intramuscular infiltrating lipoma, while maintaining excellent improvement in functional outcomes and pain after rTSA.