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An Aotus-Plasmodium falciparum model was used to determine if chloroquine resistance could be reversed in vivo. The putative resistance modulators tested all reverse chloroquine resistance in vitro and included verapamil, chlorpromazine, prochlorperazine, cyproheptadine, ketotifen, a tiapamil analog (Ro 11-2933), and a chlorpromazine analog (SKF 2133-A). Combinations of chloroquine plus chlorpromazine or prochlorperazine confirmed reversal of chloroquine resistance as exhibited by cures obtained in six Aotus monkeys infected with chloroquine-resistant P. falciparum (Vietnam Smith/RE strain) and rapid clearance of parasitemia, followed by recrudescence in six additional monkeys. The results indicate the following order of in vivo efficacy for reversing chloroquine resistance in Aotus: chlorpromazine > prochlorperazine ≫ desipramine ≫ Ro 11-2933 (tiapamil analog) > ketotifen. Cyproheptadine and verapamil were not effective in reversing chloroquine resistance and probable drug toxicity was observed with these drugs in combination with chloroquine.