Reduction mammaplasty (RM) has become established as the standard effective method for treating macromastia, but reports on the risk factors that predispose to postoperative complications have been conflicting. This meta-analysis aimed to pool the available data to identify predictors of complications following RM. The PubMed, Web of Science, Embase, and Cochrane databases were screened from inception to 1 Jan 2022, and studies were included based on predefined criteria. The perioperative risk factors BMI, smoking, age, diabetes, radiation therapy, and tissue resection weight were extracted and their correlation with complications assessed. A total of 40 studies comprising of 5908 patients were included. BMI ≥ 30kg/m2 (OR = 1.65, 95% CI 1.35-2.02; p < 0.01) and ≥ 40kg/m2 (OR = 1.97, 95% CI 1.26-3.08; p < 0.01), smoking (OR = 2.57, 95% CI 2.01-3.28; p < 0.01), diabetes (OR = 2.21, 95% CI 1.19-4.07; p < 0.05), a unilateral resection weight ≥ 1000g (OR = 1.76, 95% CI 1.02-3.05; p < 0.05), and radiation therapy (OR = 11.11, 95% CI 2.01-3.28; p < 0.01) were associated with higher rates of postoperative complications. Obese patients (BMI ≥ 30kg/m2) were more likely to experience fat necrosis (OR = 3.00, 95% CI 1.37-6.57; p < 0.01) and infection (OR = 1.66, 95% CI 1.15-2.40; p < 0.05). Smokers had a 2.03 times higher risk of infection (95% CI 1.24-3.31; p < 0.01) and 2.34 times higher risk of dehiscence (95% CI 1.38-3.98; p < 0.01). No association between complication occurrence and age 40 or 50 years or total tissue resection weight ≥ 1000g was identified. This meta-analysis provides evidence that obesity, smoking, diabetes, unilateral resection weight ≥ 1000g, and preoperative radiation therapy predispose to complication occurrence in RM. This information can optimize the ability of surgeons to provide preoperative patient education, perioperative assessment, and postoperative care planning. 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 .