Background: Combination of pertuzumab (Pmab) with trastuzumab (Tmab) has dramatically improved patients’ outcomes compared to Tmab as 1^st line therapy in HER2-positive (+ve) locally advanced (LA)/metastatic breast cancer (MBC). However, it is unclear whether reexposure to this dual HER2-blockade is more effective than conventional treatment in HER2+ve LA/MBC patients previously receiving Pmab, Tmab, and chemotherapy (CT). Methods:Trial design: PRECIOUS (NCT02514681) is a multicenter randomized open-label phase III study enrolling HER2+ve LA/MBC patients pretreated with Pmab, Tmab, and CT. Patients are randomized 1:1 to receive CT of physician’s choice (docetaxel, paclitaxel, nab-paclitaxel, vinorelbine, or eribulin) plus Tmab with or without Pmab. Eligibility criteria: Patients received Pmab, Tmab, and CT for HER2+ve LA/MBC as 1^st and/or 2^nd line anti-HER2-containing CT. The latest regimen before enrollment does not include Pmab. The number of previous CT regimens for LA/MBC does not exceed three. Aims: The primary endpoint is investigator-assessed progression-free survival (PFS). Secondary endpoints include independent reviewer-assessed PFS, PFS in patients treated with T-DM1 as the latest regimen, response rate, duration of response, overall survival, safety, and patient-reported outcome. Translational researches using blood samples are also planned to find prognostic and predictive markers for patients receiving anti-HER2 treatment. Statistics: PFS between control arm (Tmab and CT) and experimental arm (Pmab, Tmab, and CT) will be compared using a log-rank test. Three-hundred and seventy patients will be enrolled that allow the observation of 325 events for 80% power to detect a hazard ratio of 0.739 at one-side 5% level of significance. Accrual status: Recruitment began in August 2015 and is expected to be completed in July 2018 in Japan. Clinical trial information: NCT02514681