<jats:title>ABSTRACT</jats:title> <jats:p> Extracts from <jats:italic>Holostylis reniformis</jats:italic> were tested in vivo against <jats:italic>Plasmodium berghei</jats:italic> and in vitro against a chloroquine-resistant strain of <jats:italic>Plasmodium falciparum</jats:italic> . The hexane extract of the roots was the most active, causing 67% reduction of parasitemia in vivo. From this extract, six lignans, including a new (7′ <jats:italic>R</jats:italic> ,8 <jats:italic>S</jats:italic> ,8′ <jats:italic>S</jats:italic> )-3′,4′-methylenedioxy-4,5-dimethoxy-2,7′-cyclolignan-7-one, were isolated and tested in vitro against <jats:italic>P. falciparum.</jats:italic> The three most active lignans showed 50% inhibitor concentrations of ≤0.32 μM. An evaluation of minimum lethal dose (30%) values showed low toxicity for these lignans in a hepatic cell line (Hep G2A16). Therefore, these compounds are potential candidates for the development of antimalarial drugs.