The present study examined the maximal rate of oxygen consumption (VO_2max) in mice acclimated to normobaric normoxia and exercised under acute hyperoxia. Two strains of mice BALBcByJ (C) and C57BL/6J (B6), and their F1 hybrid differ in their capacity for hypoxic exercise tolerance (HET), and this difference is influenced by two genetic loci of major effect as well as an unknown number of modifying genes (McCall and Frierson, 1997). The three strains have been previously shown to have only moderate differences in HET following acclimation to normoxia. However, following eight weeks of acclimation to hypoxia, there was minimal effect on HET in C mice, increased HET in B6 mice, and dramatic improvement in HET in F1 mice. The present study investigated the three strains acclimated to normoxia and subjected to acute hyperoxia during treadmill exercise where VO_2max was determined. The goal was to determine whether there were differences in the capacity for oxygen delivery to the muscles that may explain the differences in HET. Exercise under hyperoxia provides the cardiovascular system with excess O₂, allowing an investigation of whether O₂ delivery is at full capacity during normoxic or hypoxic exercise. If so, applying hyperoxic gas during exercise should have no effect on VO_2max. Similar to a previous study where exercise was conducted under hypoxia (Sarkar, 2005) and normoxia (Ballard, 2005), the F1 and C strains of mice had high VO_2max values and the B6 mice had the lowest VO_2max during hyperoxic exercise. These results are consistent with the pattern of VO_2max observed previously during both normoxic and hypoxic exercise. The low VO_2max found in B6 mice under hyperoxic exercise was expected based on this strain’s poor endurance during bouts of normoxic exercise (Lightfoot et al., 2001). However, these results are inconsistent with the high HET of B6 mice following normoxic acclimation compared to the other two strains. The F1 mice, which have an intermediate HET when acclimated to normoxia, but the highest HET when acclimated to hypoxia, had the highest VO_2max and attained the highest maximum belt speeds during exercise under acute hyperoxia. This implies that the F1 hybrid mice have normoxic or hyperoxic endurance that is superior to the parent strains, although this was not measured in this study. In all strains, VO_2max during normoxic exercise (Ballard, 2005) was much higher than that under hypoxic exercise (Sarkar, 2005). However, the present study found that hyperoxia led to no additional increase in VO_2max, which suggests that under normoxic conditions, the O₂ delivery system is functioning at maximum capacity in all strains. These results also imply that interpretation of VO₂ and VO_2max during hyperoxic exercise must be interpreted in the context of genetic background.