Introduction Pioneers have shown that it is possible to reconstruct a full breast using just autologous fat harvested by liposuction or autologous fat transfer (AFT). This study describes the first multicentre randomised study protocol to thoroughly investigate the effectiveness of AFT to reconstruct full breasts following mastectomy procedures (primarily and delayed). Methods and analysis This study is designed as a multicentre, randomised controlled clinical superiority trial with a 1:1 allocation ratio. A total of 196 patients (98 patients per treatment arm) are aimed to be included. Patients who wish to undergo breast reconstruction with either one of the two techniques are randomly allocated into the AFT group (intervention) or the tissue-expander/prosthesis group (control). The primary outcome measure for the quality of life is measured by the validated BREAST-Q questionnaire. Ethics and dissemination Approval for this study was obtained from the medical ethics committee of Maastricht University Medical Centre/Maastricht University; the trial has been registered at ClinicalTrials.gov. The results of this randomised controlled trial will be presented at scientific meetings as abstracts for poster or oral presentations and published in peer-reviewed journals. Trial status Enrolment into the trial has started in October 2015. Data collection and data analysis are expected to be completed in December 2021. Trial registration number NCT02339779.