The resurgence and spread of antimalarial drug resistance is one of the causes of the worldwide increase of malaria. In Colombia, uncomplicated Plasmodium falciparum malaria has been treated with a combination of amodiaquine (AQ) and sulfadoxine/pyrimethamine (SP) since 2000. The efficacy of these two antimalarials was evaluated after the implementation of the new malaria treatment scheme. In the municipalities of El Charco and Tumaco (Nariño) on the Pacific Coast region, the standard PAHO protocol was used to evaluate antimalarial efficacy in areas of low to moderate malaria transmission. Patients were randomly allocated to treatment regime in two cities of Nariño, El Charco (n = 48) and Tumaco (n = 50). After 14 days none of El Charco patients presented therapeutic failure to either antimalarial. However, in Tumaco after 28 days, 12 of 24 (95% CI: 30.6-69.4) patients presented AQ treatment failure while 4 of 26 (95% CI: 5.1-33.1) patients had SP treatment failure. The high level of AQ treatment failure in Tumaco was unexpected because it had been introduced only recently as an antimalarial treatment in Colombia. The results suggest that the use of the current dose of AQ in combination with SP will be therapeutically useful for less time than expected. Use of combined therapies is a key strategy to delay antimalarial resistance. Unfortunately, its success depends on the efficacy of antimalarial drugs individually.