Two interactions of two potent blood schizontocides, pyronaridine and artemisinin, were assessed in mice infected with chloroquine-resistant Plasmodium yoelii ssp. NS or one of two lines derived from it, namely ART, which is resistant to artemisinin and SPN, which is resistant to pyronaridine. While the drug combination proved to be only additive in its action against P. yoelii ssp. NS, a marked potentiation between the two compounds was observed against the ART and SPN lines. The implications of the findings in terms of the impeding of drug resistance when these compounds are deployed for the treatment of multi-drug-resistant P. falciparum are discussed.