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Multidrug resistance of Plasmodium falciparum is spreading throughout Africa. In Lambarene, Gabon where chloroquine-resistant malaria is prevalent, a randomized comparative trial with three regimens for treating P. falciparum malaria in adults was performed. One hundred two patients evaluated received either a new micronized formulation of halofantrine (8 mg/kg every 6 hr in three doses) (group H) or chloroquine (25 mg/kg for a 48-hr period) plus clindamycin (5 mg/kg every 12 hr in six doses) (group CCI), or chloroquine (as above) plus doxycycline (2 mg/kg every 12 hr in six doses) (group CD). All treatment regimens were well-tolerated. In group H, 100% of the patients were cured, and in group CCI, 97% of the patients were cured by day 28 of follow-up. In group CD, a significantly lower cure rate of 75% (P < 0.01) and a slower parasite clearance was observed, but only low grade (RI) resistance occurred.