In Liberia, little information is available on the efficacy of antimalarials against Plasmodium falciparum malaria. We measured parasitological resistance to chloroquine and sulfadoxine-pyrimethamine (SP) in Harper, south-west Liberia in a 28-d study in vivo. A total of 50 patients completed follow-up in the chloroquine group, and 66 in the SP group. The chloroquine failure rate was 74.0% (95% confidence interval [95% CI] 59.7-85.4%) after 14 d of follow-up and 84.0% (95% CI 70.9-92.8%) after 28 d (no polymerase chain reaction [PCR] analysis was performed to detect reinfections in this group). In the SP group, the failure rate was 48.5% (95% CI 36.2-61.0%) after 14 d and 69.7% (95% CI 57.1-80.4%) after 28 d, readjusted to 51.5% (95% CI 38.9-64.0%) after taking into account reinfections detected by PCR. Genomic analysis of parasite isolates was also performed to look for point mutations associated with resistance. Genotyping of parasite isolates revealed that all carried chloroquine-resistant K-76T mutations at gene pfcrt, whereas the triple mutation (S108N, N511, C59R) at dhfr and the A437G mutation at dhps, both associated with resistance to SP, were present in 84% and 79% of pretreatment isolates respectively. These results seriously question the continued use of chloroquine and SP in Harper and highlight the urgency of making alternative antimalarial therapies available. Our study confirms that resistance to chloroquine may be high in Liberia and yields hitherto missing information on SP.