Background <p>Malaria during pregnancy remains an important cause of maternal and neonatal morbidity and mortality in sub-Saharan Africa. Currently, intermittent preventive therapy with sulphadoxine–pyrimethamine (IPTp-SP) is the standard of care. However, increasing resistance of Plasmodium falciparum to sulphadoxine–pyrimethamine (SP) raises concerns about its effectiveness. Recently, Dihydroartemisinin–piperaquine (DP), an artemisinin-based combination therapy with prolonged post-treatment prophylactic activity, has demonstrated superior parasitological efficacy compared with SP. Despite these reductions in parasitaemia, improved pregnancy outcomes have not been consistently observed. Moreover, sulphadoxine–pyrimethamine may confer additional non-malarial benefits, including antibacterial and anti-inflammatory effects. Therefore, combining SP with DP may provide additive or synergistic benefits by enhancing parasite clearance while preserving SP's ancillary advantages. This trial will evaluate the effectiveness, safety, pharmacokinetic profile, and pregnancy outcomes of IPTp-SP, IPTp-DP, and the combined IPTp-SP + DP among pregnant women in Northern Nigeria.</p> Methods <p>This study is an open-label, randomized, three-arm, parallel-group, phase IV superiority trial enrolling 1,200 HIV-negative pregnant women between 16 and 26&#xa0;weeks’ gestation in Northern, Nigeria. Participants are randomized in a 1:1:1 ratio to receive monthly IPTp with SP alone, DP alone, or SP plus DP. The primary outcome is the prevalence of maternal malaria at delivery, defined as peripheral and/or placental malaria infection detected by microscopy and/or polymerase chain reaction (PCR). Secondary outcomes include maternal anaemia, placental malaria, low birth weight, preterm birth, stillbirth, neonatal morbidity, pharmacokinetic measurements of piperaquine, biomarkers of placental dysfunction, maternal immune responses, molecular markers of antimalarial resistance, and maternal and neonatal adverse events. Participants will be followed prospectively from enrolment until delivery. Data will be analysed according to the intention-to-treat principle using regression-based comparative analyses adjusted for clinically relevant covariates.</p> Discussion <p>This trial will generate robust clinical, molecular, pharmacokinetic, and immunological evidence regarding alternative IPTp strategies in an area with emerging SP resistance. By integrating parasitological, maternal, placental, and neonatal outcomes, the study seeks to determine whether DP alone or in combination with SP provides clinically meaningful advantages over the current standard of care.</p> Trial registration <p>Pan African Clinical Trials Registry, PACTR202406478822577 registered on 18th June 2024, <a href="http://pactr.samrc.ac.za/Researcher/TrialRegister.aspx?TrialID=28360">http://pactr.samrc.ac.za/Researcher/TrialRegister.aspx?TrialID=28360</a></p>