Quechua in the Andes may be genetically adapted to altitude and able to resist decrements in maximal O2 consumption in hypoxia (ΔV̇O2 max). This hypothesis was tested via repeated measures of V̇O2 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 ΔV̇O2 max after control for covariate effects, including sea level V̇O2 max and the decrement in arterial O2 saturation measured at V̇O2 max (ΔSpO2 max) (R2 for admixture and covariate effects ∼0.80). The genetic effect reflected a main effect of admixture on ΔV̇O2 max (P = 0.041) and an interaction between admixture and ΔSpO2 max (P = 0.018). Admixture predicted ΔV̇O2 max only in subjects with a large ΔSpO2 max (P = 0.031). In such subjects, ΔV̇O2 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 ΔV̇O2 max only in subjects with a large decrease in ventilatory threshold. These findings suggest that the genetic effect on ΔV̇O2 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.