We evaluated amodiaquine as a replacement drug for treating falciparum malaria in an area of Pakistani Punjab where chloroquine-resistant Plasmodium falciparum has recently emerged. Amodiaquine appeared to be 4 to 8 times more effective than chloroquine when P. falciparum isolates were tested in vitro. However, the recrudescence rate was greater than 50% after oral treatment with 20 mg/kg amodiaquine given over two successive days. This lack of therapeutic response from amodiaquine may have been due to selection of resistant parasites in the villages where the study was performed through extensive use of chloroquine for presumptive malaria treatment during the preceding 18 months. We conclude that amodiaquine is not a suitable replacement for chloroquine for treating falciparum malaria in our study area despite in vitro sensitivity data suggesting that it would be efficacious. Baseline in vitro sensitivity to mefloquine is also reported.