In the face of an increasing prevalence of Plasmodium falciparum resistant to chloroquine and to pyrimethamine-sulphonamide or -sulphone mixtures, the need for a new, effective blood schizontocide for treatment of acute malaria is urgent. The only such compound that is almost ready for release is mefloquine (M) but there is already a danger that parasites may become resistant to this compound if it is used extensively alone. Earlier studies using a rodent model indicated that mefloquine could be 'protected' by administering it with a pyrimethamine-sulfadoxine (PS) mixture, but the experimental technique used was open to criticism. The present experiments, using a relapse technique to develop drug resistance, more closely parallel the way antimalarials are likely to be deployed in human communities. They confirm that the development of resistance to the individual components in the P. berghei N line is delayed by the triple combination, and more so in the slightly chloroquine-resistant 'P. berghei NS' line. The combination did not prevent the development of resistance in a line initially resistant to PS, but the level reached was much less than those seen when P. berghei N or 'P. berghei NS' were exposed to MPS or to M alone. It was concluded that the use of a triple combination of M, P and S against P. falciparum would be of value in 'protecting' these compounds, and thus gain time while new agents against malaria are being developed.