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Total shoulder arthroplasty is increasingly used in the treatment of arthritis. However, the effect of total shoulder arthroplasty on health-related quality of life has not been fully established. The goal of this systematic review and meta-analysis was to characterize the change in generic and shoulder-specific health-related quality-of-life measures resulting from total shoulder arthroplasty.We identified published studies reporting preoperative and postoperative health-related quality-of-life outcomes for patients receiving total shoulder arthroplasty. Health-related quality-of-life measures were identified, and meta-analysis was used to calculate standardized mean differences (SMDs, reflective of the effect size) and 95% confidence intervals for each scale.Twenty studies (1576 total shoulder replacements) met the inclusion criteria. Outcome measures were analyzed after an average postoperative follow-up duration of 3.7 ± 2.2 years. The Short Form-36 demonstrated significant improvement in physical component summary scores (SMD = 0.7, p < 0.001) but not in mental component summary scores (SMD = 0.2, p = 0.37). Significant improvements were observed in the visual analog scale score for pain (SMD = −2.5, p < 0.001) and scores on three shoulder-specific measures: the Constant score (SMD = 2.7, p < 0.001), American Shoulder and Elbow Surgeons score (SMD = 2.9, p < 0.001), and Simple Shoulder Test (SMD = 2.3, p < 0.001).Total shoulder arthroplasty leads to significant improvements in scores for function and pain. Shoulder-specific measures of function consistently showed the greatest degree of improvement, with large effect sizes. Total shoulder arthroplasty also leads to significant improvements in overall physical well-being, with a moderate-to-large effect size.Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.