Background: Reverse total shoulder arthroplasty (rTSA) is an established procedure for cuff tear arthropathy. More lateralized prostheses have been designed to overcome the reported adverse outcomes of Grammont-style rTSA. Purpose: To compare the clinical and radiological outcomes of medialized and lateralized center of rotation (COR) in rTSA. Study Design: Systematic review; Level of evidence, 3. Methods: This review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Included were studies with a level of evidence ≥3 that compared medialized and lateralized rTSA with a minimum follow-up of 12 months. Functional scores including the American Shoulder and Elbow Surgeons (ASES) score and Constant score (CSS), range of motion at final follow-up, gain of external rotation (ER), visual analog scale (VAS) pain score, scapular notching, and heterotopic ossification (HO) were compared. Data were analyzed using random-effects or fixed-effects models in accordance with heterogeneity. Results: Five retrospective cohort studies and 1 randomized controlled study (n = 594 patients) were included. Lateralized rTSA resulted in greater improvement in ER degree ( P < .001), a lower VAS pain score (standardized mean difference [SMD], –0.39; P = .002), and a lower rate of scapular notching (risk ratio [RR], 0.40; P < .001) and HO (RR, 0.52; P < .001). Final forward flexion (SMD, –0.14; P = .629) and ER (SMD, 0.21; P = .238) did not differ significantly between the 2 groups. Overall functional scores, including ASES score (SMD, 0.22; P = .310) and CSS (SMD, 0.37; P = .077), also did not differ significantly (SMD, 0.28; P = .062). The overall complication rate did not differ significantly between the 2 groups (RR, 0.71; P = .339). Conclusion: Compared with medialized rTSA, lateralized COR rTSA results in greater improvement in ER and the VAS pain score, decreased rates of scapular notching and HO, and no significant changes in functional outcome scores or the complication rate.