One approach to investigate if human genetic variation influences the selection of Plasmodium falciparum drug resistance is to compare the frequency of resistant infections among human populations differing in their genetic background and living in the same epidemiological context. A further complementary approach consists in comparing drug resistance among subjects differing for genes involved in drug metabolism. Here we report, from malariological surveys performed in Burkina Faso, that the prevalence of P. falciparum chloroquine-resistant infections (pfcrt 76T and/or pfmdr1 86Y alleles) differs among sympatric ethnic groups, being higher in the Mossi and Rimaibé groups than in the Fulani group (odds ratio [OR], 2.24; 95% confidence interval [CI], 1.27–3.92; P = .007). The association analysis revealed that the human CYP2C8*2 variant, known to determine a poor drug metabolizer phenotype, was associated with P. falciparum chloroquine-resistant infections (OR, 1.66; 95% CI, 1.13–2.43; P = .008). This variant is more frequent in the Mossi-Rimaibé group (23.7% ± 1.4%) than in the Fulani group (9.9% ± 2.5%; P = .0003). This study provides an example of how host genetic variation may influence the selection dynamics of a pathogen’s drug resistance.