Abstract Background The emphasis on aesthetic outcomes and quality of life (QoL) has motivated surgeons to develop skin- and nipple-sparing mastectomy (SSM/NSM) for breast cancer (BC) treatment or prevention. Immediate breast reconstruction is based on implants or autologous tissue. The optimal positioning of the implant is not clear: While pre-pectoral positioning respects the anatomic position of the mammary gland and avoids surgery-induced alterations of the pectoralis major muscle, the lack of muscle coverage may increase the risk of additional surgical interventions due to major complications. The Oncoplastic Breast Consortium (OPBC) identified this knowledge gap as research priority in 2019. Trial design International, multicenter study with a superiority trial design and two parallel groups with 1:1 random allocation to pre- or sub-pectoral implant-based breast reconstruction (IBBR). Following a pragmatic approach, randomly assigned IBBR will be performed according to the surgeons’ usual care by use of a one- or two-stage approach with or without adjunctive mesh. Follow-up visits are performed within routine care (visits at 10 days and at 1, 6, 12, 18 and 24 months after surgery). Oncological follow-up will be conducted annually for 10 years. ClinicalTrials.gov identifier: NCT04293146. Eligibility We include women ≥ 18 years, with an indication for NSM or SSM and IBBR in the therapeutic or risk-reducing setting, the ability to complete QoL questionnaires and the adequateness of skin flap(s) for pre-pectoral IBBR (intraoperative decision of the surgeon). Specific aims The primary objective is to test whether pre-pectoral IBBR provides better QoL with respect to long-term (24 months) physical well-being of the chest (BREAST-Q) compared to sub-pectoral IBBR for patients undergoing SSM or NSM for prevention or treatment of BC. Secondary endpoints include loss of expander or implant, complications, other BREAST-Q QoL and patient satisfaction domains, aesthetic outcomes and recurrence free survival. Interference of different dose distributions of radiation therapy and its consequences on the distribution of local tumor recurrences will be assessed. Statistical methods The primary analysis will be performed on the full analysis set following the intention-to-treat principle. To test the primary hypothesis, a linear mixed model will be fitted with the BREAST-Q score as response variable and treatment assignment as independent variable. The analysis will be adjusted for baseline BREAST-Q score, stratification factors (i.e. uni- vs bilateral surgery and NSM vs SSM) and other potential confounders. A random intercept to account for the center effect will be included. As a sensitivity analysis, an unadjusted t-test will be performed on the BREAST-Q score change from baseline to compare the two treatment arms. The sample size was determined for the primary endpoint, with an expected mean score of 76 points for sub-pectoral and 80 points for pre-pectoral implants. The clinically relevant difference to be detected in this superiority design is 4 points, with an expected common standard deviation of 13 points. A sample size of 334 patients provides an 80% power for a two-sided t-test at level α = 0.05. Compensating for a 10% dropout rate, the total sample size was calculated to include 372 patients. Present accrual and target accrual By June 2020, one study site (Basel) has been initiated. During a 21-month recruitment period, we plan to include 372 patients at 21 sites in Switzerland, USA, China, Austria, Germany, Hungary and Sweden. Contact information Prof. Dr. Walter Paul Weber, Chefarzt Brustchirurgie, Breast Surgeon SSO, Universitätsspital Basel, Spitalstrasse 21, CH-4031 Basel, Tel: +41 61 328 61 49, Walter.Weber@usb.ch Citation Format: Walter Paul Weber, Elisabeth A Kappos, Meredith M Regan, Giusi Moffa, Yves Harder, Karin Ribi, Shelley Potter, Andrea Pusic, Mathias K Fehr, Lars G Hemkens, Thomas Holzbach, Jian Farhadi, Colin Simonson, Michael Knauer, Ralph Verstappen, Heiner Bucher, Daniel Zwahlen, Frank Zimmermann, Matthias Schwenkglenks, Rosine Mucklow, Vesna Bjelic-Radisic, Amelia Chiorescu, Yoon Chun, Subrina Farah, Xiasong Chen, Linda Nigard, Sherko Kümmel, Roland Reitsamer, Maik Hauschild, Ilario Fulco, Christoph Tausch, Thomas Fischer, Dimitri Sarlos, Mihai Constantinescu, Judith E Lupatsch, Florian Fitzal, Joerg Heil, Zoltán Mátrai, Jana de Boniface, Christian Kurzeder, Martin Haug, Alexandra Schulz. Pre- versus sub-pectoral implant-based breast reconstruction after skin-sparing mastectomy or nipple-sparing mastectomy (OPBC-02 PREPEC): A pragmatic, multicenter, randomized, superiority trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-23-03.