In 2003, the high level of chloroquine (CQ) treatment failure for uncomplicated Plasmodium falciparum malaria cases has led Senegal to adopt a new combination therapy with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ). From September through November 2004, we used the 14-day World Health Organization follow-up protocol to assess the therapeutic response in patients with uncomplicated P. falciparum malaria in an area of high prevalence of pfcrt T76 mutant allele and SP resistance mutations. Of the 82 patients who were recruited, 68 (82.9%) completed follow-up. The response of the patients to treatment was adequate clinical response for 63 out of 68 patients (92.6%), while five (7.4%) clinical failures were recorded, four early treatment failures, and one late treatment failure. The prevalence of the pfcrt T76 allele at day 0 was 59.5%. The two-sided Fisher's exact test did not show an association between pfcrt T76 allele and treatment failure (p=0.167). The transitory treatment is effective and safe. However, the presence of high levels of mutant alleles points out the need to closely monitor the new therapeutic regimen.