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. 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 and 10 mm of humeral lateralization and glenosphere lateralization) on deltoid force and joint load during abduction with and without rotator cuff repair were assessed. RESULTS Deltoid force was significantly affected by increasing humeral lateralization (-2.5% ± 1.7% body weight [BW], P = .016) and glenosphere lateralization (+7.7% ± 5.6% BW, P = .016). Rotator cuff repair interacted with humeral and glenosphere lateralization (P = .005), such that with no humeral lateralization, glenosphere lateralization increased deltoid force without cuff repair (8.1% ± 5.1% BW, P = .012). This effect was increased with cuff repair (12.8% ± 7.8% BW, P = .010), but the addition of humeral lateralization mitigated this effect. Rotator cuff repair increased joint load (+11.9% ± 5.1% BW, P = .002), as did glenosphere lateralization (+13.3% ± 3.7% BW, P < .001). These interacted, such that increasing glenosphere lateralization markedly increased the negative effects of cuff repair (9.4% ± 3.2% BW [P = .001] vs. 14.4% ± 7.4% BW [P = .005]). CONCLUSION Rotator cuff repair, especially in conjunction with glenosphere lateralization, 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. Humeral lateralization improves joint compression through deltoid wrapping and increases the deltoid's mechanical advantage, and therefore, could be used in place of rotator cuff repair, thus avoiding its complications.