The in vitro activities of doxycycline, chloroquine, quinine, amodiaquine, artemether, pyrimethamine, and cycloguanil were evaluated against Plasmodium falciparum isolates from Senegal (Dielmo and Ndiop), using an isotopic, micro, drug susceptibility test. The 71-50% inhibitory concentration (IC50) values for doxycycline ranged from 0.7 to 108.0 microM and the geometric mean IC50 for the 71 isolates was 11.3 microM (95% confidence interval = 9.5-13.4 microM). The activity of doxycycline did not differ significantly (P = 0.0858) between the chloroquine-susceptible isolates and the chloroquine-resistant isolates. There was no in vitro correlation between the responses to doxycycline and those to artemether, chloroquine, quinine, amodiaquine, pyrimethamine, and cycloguanil, suggesting no in vitro cross-resistance among these drugs. Potency was increased by prolonged exposure. In 96-hr incubations, the activity of doxycycline was 4-5-fold more increased than in 48-hr incubations. The in vitro activity of doxycycline against intraerythrocytic stages of multidrug-resistant P. falciparum, its action against the preerythrocytic forms, the lack of correlation between the responses in vitro of P. falciparum to doxycycline and the other antimalarial drugs, and its original potential site of action are factors that favor its use as antimalarial drug.