To determine whether dihydroartemisinin-piperaquine (DHA-PPQ) is non-inferior to artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria infection in pregnancy. 417 second/ third trimester pregnant women with confirmed asymptomatic Plasmodium falciparum parasitaemia were randomized to receive DHA-PPQ or ASAQ over 3 days. Women were followed up on days 1, 2, 3, 7, 14, 28 and 42 after treatment start and at delivery for parasitological, haematological, birth outcomes and at 6-weeks post-partum to ascertain the health status of the babies. Parasitological efficacy (PE) by days 28 and 42 were co-primary outcomes. Analysis was per-protocol (PP) and modified intention-to-treat (ITT). Non-inferiority was declared if the two-sided 95% confidence interval for PE at the endpoints excluded 5% lower efficacy for DHA-PPQ. Secondary outcomes were assessed for superiority. In PP analysis, PE was 91.6% for DHA-PPQ and 89.3% for ASAQ by day 28 and 89.0% and 86.5% respectively by day 42. DHA-PPQ was non-inferior to ASAQ with respect to uncorrected PE {adjusted difference by day 28 (DHA-PPQ-ASAQ); 3.5% (95%CI: -1.5, 8.5) and day 42: 3.9% (95%CI: -2.7, 10.4)}. ITT analysis gave similar results. PCR to distinguish recrudescence and reinfection was unsuccessful. DHA-PPQ recipients had fewer adverse events of vomiting, dizziness and general weakness compared to ASAQ. Both drugs were well-tolerated and there was no excess of adverse birth outcomes. DHA-PPQ was non-inferior to ASAQ for treatment of malaria infection during pregnancy. No safety concerns were identified. Our findings contribute to growing evidence that DHA-PPQ is useful for control of malaria in pregnancy. This article is protected by copyright. All rights reserved.