Oxygen kinetics in fibroblasts was biphasic. This was quantitatively explained by a major mitochondrial hyperbolic component in the low-oxygen range and a linear increase of rotenone- and antimycin A-inhibited oxygen consumption in the high-oxygen range. This suggests an increased production of reactive oxygen species and oxidative stress at elevated, air-level oxygen concentrations. The high oxygen affinity of mitochondrial respiration provides the basis for the maintenance of a high aerobic scope at physiological low-oxygen levels, whereas further pronounced depression of oxygen pressure induces energetic stress under hypoxia.