BACKGROUND: Arthropod vectors feeding on the blood of individuals treated with ivermectin have substantially increased mortality. Whether this effect will translate into a useful tool for reducing malaria burden at scale is not clear. Our trial aimed to assess whether using ivermectin as an adjunct to mass drug administration (MDA) with dihydroartemisinin-piperaquine would further reduce malaria prevalence. METHODS: MATAMAL was a quadruple-blinded, cluster-randomised, placebo-controlled trial, conducted on the Bijagos Archipelago, Guinea-Bissau, an area of seasonal malaria transmission. All residents were invited to participate, with exclusions for drug safety. 24 clusters were randomised in a 1:1 ratio, using restriction randomisation, to either MDA with three daily oral doses of dihydroartemisinin-piperaquine and ivermectin (300 μg/kg per day) in three sequential months during the transmission season in 2021 and 2022, or MDA with dihydroartemisinin-piperaquine and placebo in the same schedule. The primary outcome was quantitative PCR prevalence of Plasmodium falciparum parasitaemia in all age groups, during peak transmission, after the second year of intervention. The primary entomological outcome was anopheline parity rate. The trial is registered with ClinicalTrials.gov (NCT04844905). FINDINGS: Participants were recruited between June 7, 2021 and Sept 21, 2022. The baseline population was 25 882 (12 634 [50·6%] were female individuals and 12 317 [49·4%] were male individuals): 13 832 were in the intervention group and 12 050 in the control group. Cluster-level coverage for dihydroartemisinin-piperaquine ranged from 60·4% to 78·7%, and for ivermectin or ivermectin-placebo from 58·1 to 77·1%. Following the intervention, the prevalence of P falciparum infection was 118 (5·05%) of 2300 in the control group and 141 (6·64%) of 2083 in the intervention group. The adjusted risk difference was 1·67% (95% CI -1·44 to 4·78; p=0·28). There were 124 adverse events in the control group (1·0% of participants) and 267 in the intervention group (1·9% of participants). Two serious adverse events were reported, neither related to the intervention, and no treatment-related deaths. The anopheline parity rate was 1679 (67·8%) of 2475 in control clusters and 1740 (72·3%) of 2414 in intervention clusters. The adjusted risk difference was -1·32 (95% CI -14·77 to 12·12; p=0·84). INTERPRETATION: Adding ivermectin to dihydroartemisinin-piperaquine MDA had no additional effect on reducing malaria prevalence or vector parity in this setting. The intervention was well tolerated. To our knowledge, this trial is the first to be designed to assess whether ivermectin has an additive effect on malaria when coadministered with dihydroartemisinin-piperaquine MDA. FUNDING: The National Institute for Health and Care Research, Medical Research Council, Wellcome, and Foreign, Commonwealth & Development Office.