Background <p>In ptotic/macromastic breasts, nipple-sparing mastectomy (NSM) risks ischemic complications. Staging with nipple repositioning (mastopexy or breast reduction) may improve perfusion, but uncertainty remains regarding safety and optimal timing.</p> Methods <p>PRISMA guidelines will be followed. 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. Meta-analysis will be performed using Review Manager 5.4 software; forest plots will be used for two-arm studies to calculate pooled risk ratios, heterogeneity using <i>I</i>² statistics, and <i>p</i>-value for overall effect.</p> Discussion <p>Due to the conflicting studies regarding the optimal timing and safety of nipple-repositioning before NSM, a systematic review and meta-analysis is required to provide more definitive evidence-based recommendations regarding the optimal timing and safety of this staged approach. Limitations may include the predominance of observational studies, heterogeneity in intervals, and inconsistent reporting that may limit the certainty of our conclusions.</p> Systematic review registration <p>ROSPERO CRD42024513738</p>