The antimalarial activity of combinations of mefloquine or artesunic acid with ciprofloxacin and other synthetic fluoroquinolone was tested in vitro against Plasmodium falciparum using a strain (BHz26/86) partially resistant to chloroquine and a resistant clone (W2); both are sensitive to mefloquine. Inhibition of parasite growth was measured in relation to controls without drugs, either by counting parasitemia in Giemsa-stained blood smears or by measuring the reduction in [(3)H]-hypoxanthine uptake. Combinations containing artesunic acid or mefloquine with ciprofloxacin had significant in vitro activity, inhibiting by more than 90% of the growth of both strains of P. falciparum at doses significantly lower than those of the antimalarials alone. When tested in mice inoculated with P. berghei chloroquine-sensitive parasites (NK65 strain), ciprofloxacin was inactive, whereas mefloquine and artesunic acid were active (IC(50)=2.5 and 4.2 mg/kg, respectively); combinations containing mefloquine at an equivalent dose of 0.5 mg/kg reduced parasitemia by 59% and artesunic acid activity was also improved by ciprofloxacin. Our data support the idea that ciprofloxacin in combination with antimalarials may be useful in the treatment of chloroquine-resistant human malaria, allowing the use of lower doses of these drugs.