Quechua in the Andes may be genetically adapted to altitude and able to resist decrements in maximal O₂consumption in hypoxia (ΔV̇o_{2 max}). This hypothesis was tested via repeated measures of V̇o_{2 max}(sea level vs. 4,338 m) in 30 men of mixed Spanish and Quechua origins. Individual genetic admixture level (%Spanish ancestry) was estimated by using ancestry-informative DNA markers. Genetic admixture explained a significant proportion of the variability in ΔV̇o_{2 max}after control for covariate effects, including sea level V̇o_{2 max}and the decrement in arterial O₂saturation measured at V̇o_{2 max}(ΔSp_{O2 max}) ( R²for admixture and covariate effects ∼0.80). The genetic effect reflected a main effect of admixture on ΔV̇o_{2 max}( P = 0.041) and an interaction between admixture and ΔSp_{O2 max}( P = 0.018). Admixture predicted ΔV̇o_{2 max}only in subjects with a large ΔSp_{O2 max}( P = 0.031). In such subjects, ΔV̇o_{2 max}was 12–18% larger in a subgroup of subjects with high vs. low Spanish ancestry, with least squares mean values (±SE) of 739 ± 71 vs. 606 ± 68 ml/min, respectively. A trend for interaction ( P = 0.095) was also noted between admixture and the decrease in ventilatory threshold at 4,338 m. As previously, admixture predicted ΔV̇o_{2 max}only in subjects with a large decrease in ventilatory threshold. These findings suggest that the genetic effect on ΔV̇o_{2 max}depends on a subject's aerobic fitness. Genetic effects may be more important (or easier to detect) in athletic subjects who are more likely to show gas-exchange impairment during exercise. The results of this study are consistent with the evolutionary hypothesis and point to a better gas-exchange system in Quechua.