Background <p>Recurrent implantation failure (RIF) remains clinically unresolved at this stage. Hydroxychloroquine, as an immunomodulator, is still lacking clinical evidence, but it is being used by increasing numbers of reproductive centers and physicians worldwide, so a well-designed randomized controlled trial (RCT) is urgently needed to elucidate whether hydroxychloroquine can improve pregnancy outcomes in patients with RIF.</p> Methods and analysis <p>In this study, we plan to recruit 686 volunteers who will undergo IVF/ICSI at 5 reproductive centers from 6 December 2022. Participants will be randomized to two parallel groups and treated with hydroxychloroquine sulfate tablets or placebo from the start of endometrial preparation to 14&#xa0;days after frozen embryo transfer (if not pregnant) or to 12&#xa0;weeks of pregnancy (if pregnant). The primary outcome is live birth rate, and the secondary outcomes include biochemical pregnancy rate, clinical pregnancy rate, embryo attachment rate, first trimester abortion rate and ongoing pregnancy rate, birth weight, pregnancy and perinatal complications, congenital anomaly, and other adverse events.</p> Discussion <p>This study aims to evaluate whether hydroxychloroquine (HCQ) improves pregnancy outcomes in patients with recurrent implantation failure (RIF). Secondary objectives include comparative analysis of gestational complications between the intervention and control groups.</p> Trial registration <p>ChiCTR2100047584 [Chinese Clinical Trial Registry (ChiCTR): registered on 20 June 2021].</p> <p>LM2021267 [Ethics Committee of Peking University Third Hospital].</p>