Background <p>Acellular dermal matrices (ADMs) have become popularly used in implant-based breast reconstruction (IBBR) due to their potential to decrease the risk of implant complications such as capsular contracture and malposition. AlloDerm and DermACELL are two of the most commonly used human ADMs, each processed differently to enhance sterility and biocompatibility. Despite their widespread use, the comparative effectiveness and safety of these ADMs remain debatable among plastic surgeons, with conflicting evidence in the literature regarding their complication profiles. This systematic review and meta-analysis aims to evaluate the clinical outcomes associated with AlloDerm versus DermACELL in breast reconstruction.</p> Methods <p>This review will follow the methodological guidance of the Cochrane Handbook for Systematic Reviews of Interventions. The database search will be conducted using MEDLINE (PubMed), Scopus, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Clinicaltrials.org targeting studies from inception to search date. Studies will be screened using inclusion and exclusion criteria and data extracted into a spreadsheet. Screening, extraction, and risk-of-bias assessments will be performed independently by two reviewers and discrepancies resolved by a third independent reviewer. Primary outcomes include complication rates (e.g., capsular contracture, infection, implant malposition), patient-reported satisfaction (BREAST-Q), and drain time. Data analysis and meta-analysis will be performed using Microsoft Excel and Review Manager 5.4 software. Heterogeneity will be assessed using the <i>I</i>² statistic. A random-effects model will be applied in cases of significant heterogeneity followed by a sensitivity analysis. This review will be reported in accordance with the PRISMA 2020 checklist.</p> Discussion <p>With the increasing use of ADMs in IBBR, it is important that surgeons have adequate evidence available to assist operative decision-making. This meta-analysis will help surgeons determine whether one ADM is better than the other. This could potentially minimize the risk of patient complications, improve patient satisfaction, and decrease unnecessary hospital readmissions or reoperations due to avoidable complications, thereby decreasing healthcare costs.</p> Systematic review registration <p>PROSPERO CRD42024542928.</p>