INTRODUCTION: In breast surgeries, prophylactic antibiotics given before the surgical incision as per Joint Commission Surgical Care Improvement Project guidelines have been shown to decrease the rate of postoperative infections. There is, however, no clear consensus on postoperative antibiotic prophylaxis in patients undergoing mastectomy with indwelling drains. This trial protocol proposes to study the difference in rates of surgical site infection (SSI) with or without continuation of postoperative antibiotics in patients undergoing mastectomy without immediate reconstruction and with indwelling drains. METHODS AND ANALYSIS: In this multicentre, double-blinded clinical trial, all patients undergoing mastectomy (without immediate reconstruction) will receive a single prophylactic dose of preoperative antibiotics at induction of anaesthesia and will then get randomised to either continue antibiotic prophylaxis or a placebo postoperatively, for the duration of indwelling drains. The primary and secondary outcomes will be development of an SSI and antibiotic-associated adverse effects, respectively. Data will be collected through a standard questionnaire by wound assessors. Intention-to-treat analysis will be carried out using STATA V.12. For categorical variables, frequencies and percentages will be assessed by χ2 test/Fishers exact test as appropriate. The quantitative variables will be computed by their mean±SD or median (IQR) and will be assessed by independent t-test/Mann-Whitney test as appropriate. Unadjusted and adjusted relative risk with their 95% CI will be reported using Cox proportional regression. A p value of <0.05 will be considered statistically significant. ETHICS AND DISSEMINATION: Ethical approval has been obtained from each sites Ethical Review Board. The study background and procedure will be explained to the study participants and informed consent will be obtained. Participation in the study is voluntary. All data will be deidentified and kept confidential. The study findings will be published in scientific media and authorship guidelines of International Committee of Medical Journal Editors will be followed. TRIAL REGISTRATION NUMBER: NCT04577846. (patient recruitment).