Intermittent exposures to normobaric or hypobaric hypoxia have been used to provide enhancements to oxygen delivery capabilities in athletes and in some patient populations as well as in the pre-acclimatization of individuals. The body is capable of very rapid adjustments to this type of environmental stress. However, it is somewhat unclear if an acute exposure to this type of environmental stress is enough to produce evidence of adaptations. PURPOSE: To examine evidence for physiological adaptation after a single bout of exercise at simulated altitude (Stratosphere Hypobaric Training Chamber) as determined from heart rate (HR), peripheral oxygen saturation (SpO2) and the ratio of hemoglobin O2 (oxygen) saturation in the circulating peripheral blood relative to HR (SpO2/HR) response. METHODS: 11 subjects (6 male, 5 female, age 36.5 ± 12.9 yrs, height 173.6 ± 9.2 cm, weight 75.7 ± 14.5 kg) completed 2 hypobaric chamber visits. During both visits, subjects performed a 30 min bout of exercise on a cycle ergometer at the same simulated altitude (2 km n = 1, 3 km n = 2, 4 km n = 8). Based on subjects previous VO2max test results, the exercise was divided into a light to moderate intensity for the first 15 min (target 50-60% WMax), immediately followed by a higher intensity (target 70-80% WMax) for the second 15 min. There was an average of 10 ± 6 days between each testing visit. Statistical analyses included paired samples t-test (p ≤ 0.05). RESULTS: There were no significant changes in workload (p = 0.28) or SpO2 (p = 0.67) between the two visits. However, there was a significant difference in HR (p < 0.001) and SpO2/HR (p < 0.001). There was an average decrease in HR of 19 bpm (12%) from visit 1 (155 ± 17 bpm) to visit 2 (136 ± 26 bpm), along with a 16% average increase in SpO2/HR from visit 1 (0.55 ± 0.06) to visit 2 (0.64 ± 0.13). The average workload across both intensity levels and altitudes were 97 ± 38 W for Visit 1 and 103 ± 39 W for Visit 2, with an average SpO2 of 84 ± 5% for both visits. CONCLUSION: These findings indicate an adaptive response to a short aerobic exercise bout during simulated altitude exposure that appears to be sustained greater than one week after the initial visit. Whether this is linked to oxygen sensing, neurally mediated or suggests early adjustments in oxygen delivery pathways is unclear, but appear unrelated to age, sex or fitness level.