In light of reports of increasing resistance of parasites to amodiaquine in African countries in whichPlasmodium falciparumis endemic as well as the paucity of recent in vitro sensitivity data, we assessed the in vivo and in vitro sensitivity to amodiaquine ofP. falciparumisolates from 128 pediatric outpatients (0.5-10 years old) in Pingilikani, Kilifi District, Kenya, who were treated with amodiaquine (10 mg/kg/day for 3 days). The polymerase chain reaction-corrected parasitological cure rate on day 28 (by Kaplan-Meier analysis) was 82% (95% confidence interval [CI], 74%-88%). Twenty-six percent (17/66) of tested pretreatmentP. falciparumfield isolates had 50% in vitro growth inhibition at concentrations of N-desethyl-amodiaquine (DEAQ)—the major biologically active metabolite of amodiaquine—above the proposed resistance threshold of 60 nmol/L, but baseline median DEAQ 50% inhibitory concentration values were not associated with subsequent risk of asexual parasite recrudescence (29 nmol/L [95% CI, 23-170 nmol/L] and 34 nmol/L [95% CI, 30-46 nmol/L] for patients with and those without recrudescences, respectively). The median absolute neutrophil count dropped by 1.3×103 cells/μL (95% CI, -1.7×103 to -0.7×103 cells/μL) between days 0 and 28. The high prevalence of in vitro and in vivo resistance precludes the use of amodiaquine on its own as second-line treatment. These findings also suggest that the value of amodiaquine combinations as first- or second-line treatment in areas with similar patterns of 4-aminoquinoline resistance should be reassessed.