Introduction: There is disagreement regarding whether, when possible, the rotator cuff should be repaired in conjunction with reverse total shoulder arthroplasty (RTSA). Therefore, we investigated the effects of rotator cuff repair in RTSA models with varying magnitudes of humeral and glenosphere lateralization (HLat & GLat). Methods: Six fresh-frozen cadaveric shoulders were tested on a validated in-vitro muscle driven motion simulator. Each specimen was implanted with a custom adjustable, load-sensing RTSA after creation of a simulated rotator cuff tear. The effects of 4 RTSA configurations (0&10mm x HLat & GLat) on deltoid force and joint load during abduction with/without rotator cuff repair were assessed. Results: Increasing HLat and GLat significantly affected deltoid force (-2.5±1.7%BodyWeight (%BW), p=0.016 & +7.7±5.6%BW, p=0.016). Rotator cuff repair interacted with HLat & GLat (p=0.005) such that with no HLat, GLat increased deltoid force without cuff repair (8.1±5.1%BW, p=0.012) and this effect was increased with cuff repair (12.8±7.8%BW, p=0.010), but addition of HLat mitigated this effect. Rotator cuff repair increased joint load (+11.9±5.1%BW, p=0.002), as did GLat (+13.3±3.7%BW, p<0.001), and these interacted such that increasing GLat markedly increases cuff repair's negative effects (9.4±3.2%BW, p=0.001 vs 14.4±7.4%BW, p=0.005). Conclusion: Rotator cuff repair, especially in conjunction with GLat, produces an antagonistic effect that increases deltoid and joint loading. The long-term effects of this remain unknown; however, combining these factors may prove undesirable. HLat improves joint compression through deltoid wrapping and increases the deltoid's mechanical advantage. Therefore, it could be used in place of rotator cuff repair, thus avoiding its complications.