BACKGROUND: The caseload of breast reduction is on the rise. Despite this popularity, the association between body mass index (BMI) and postoperative outcomes remains unclear. We hypothesize that BMI is a significant determinant of postoperative morbidity after breast reduction and leverage a multi-institutional database to investigate this correlation. METHODS: We queried the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) (2008-2022) to identify female adult patients who underwent breast reduction. We categorized all patients into six BMI subgroups, and compared their outcomes (i.e., 30-day surgical and medical complications, reoperation, readmission, and mortality) via multivariate logistic regression analyses. RESULTS: 45,373 patients (mean age: 40 ± 14 years; mean BMI: 31 ± 6.1 kg/m) were identified, of whom 0.1% (n = 61) were underweight, 12% (n = 5635) healthy weight, 34% (n = 15,346) overweight, 30% (n = 13,795) had obesity I, 15% (n = 6843) obesity II, and 8.1% (n = 3693) obesity III. Overall, 2881 (6.4%) patients experienced complications, with 1936 (4.3%) cases of surgical complications and 317 (0.7%) cases of medical complications. The risk for complications increased stepwise above the healthy BMI range. Compared to women with healthy weight, patients with obesity I, II, and III had a significantly higher risk of any complication (OR 1.5, p < 0.001; OR 1.87, p < 0.001; and OR 2.6, p < 0.001, respectively), medical complications (OR 2.4, p = 0.005; OR 2.99, p = 0.001; and OR 5.2, p < 0.001, respectively), and surgical complications (OR 2.2, p < 0.001; OR 2.81, p < 0.001; and OR 4.2, p < 0.001, respectively). Overweight patients were also at higher risk for any complication (OR 1.2, p = 0.09), medical complications (OR 2.1, p = 0.02), and surgical complications (OR 1.4, p = 0.004). The odds for reoperation did not increase with higher BMI classes. CONCLUSION: Our multi-institutional data analysis revealed a significant correlation between elevated BMI and the occurrence of both surgical and medical complications after breast reduction surgery. The postoperative risk increased progressively with BMI above the healthy range. These findings are essential for informing preoperative counseling, refining risk assessment, and developing tailored protocols. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors  www.springer.com/00266 .