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Abstract Introduction In reverse shoulder arthroplasty (RSA) new designs enable greater amounts of lateralization to prevent instability and scapular notching and increase range of motion, however, excessive lateralization leads to stress upon the acromion that can result in scapular spine fatigue fractures. Aim of this study was to gender- and size-specifically assess the influence of glenosphere size and different humeral designs on lateralization, distalization, and bony impingement-free range of motion (ROM) in patients undergoing RSA. Methods Computed tomography scans from 30 osteoarthritic patients (f:15, m:15) and 20 cuff tear arthropathy patients (f:10, m:10) were used to virtually simulate RSA implantation. The efficacy of an inlay Grammont-type system vs. an onlay lateralizing system combined with different glenosphere sizes (36 mm vs. 42 mm) in achieving ROM, lateralization, and distalization was evaluated. Moreover, gender and patient’s constitution were correlated to humeral size by radiologically measuring the best-fit circle of the humeral head. Results A different amount of relative lateralization was achieved in both genders using large glenospheres and onlay designs. Latter yielded a higher ROM in all planes for men and women with a 42 mm glenosphere; with the 36 mm glenosphere, an increased ROM was observed only in men. The 155° inlay design led to joint medialization only in men, whereas all designs led to lateralization in women. When adjusting the absolute amount of lateralization to humerus’ size (or patient’s height), regardless of implant type, women received greater relative lateralization using 36 mm glenosphere (inlay: 1%; onlay 12%) than men with 42 mm glenosphere (inlay: -3%; onlay: 8%). Conclusion The relative lateralization achieved using onlay design is much higher in women than men. Small glenospheres yield greater relative lateralization in women compared to large glenospheres in men. Humeral lateralization using onlay designs should be used cautiously in women, as they lead to great relative lateralization increasing stress onto the acromion. Level of evidence Basic Science Study, Computer Modeling.