We tested the hypothesis that maximal exercise performance in adults with cystic fibrosis is limited by arterial hypoxemia. In study 1, patients completed two maximal exercise tests, a control and a test with 400cm³ of added dead space. Maximal oxygen consumption was significantly lower in the added dead space study (1.04 ± 0.15 l/min v 1.20 ± 0.11 l/min, p<0.05) versus control, with no difference in peak ventilation. There was significant oxygen desaturation during exercise that was equal in both control and added dead space studies. The decrease in maximal oxygen consumption with added dead space suggests that maximal exercise in cystic fibrosis is limited by respiratory factors. We subsequently examined whether pulmonary mechanics or arterial hypoxemia limit maximal exercise performance. In study 2, patients completed two maximal exercise tests, a control and a test with 400cm³ of added dead space while also breathing 38% O₂. Added dead space was used to overcome the suppressive effects of hyperoxia on VE. Maximal oxygen consumption was significantly higher with added dead space and 38% O₂ versus control (1.62 ± 0.16 l/min v 1.43 ± 0.14 l/min, p<0.05). Peak ventilation and oxygen saturation were significantly greater in the added dead space and 38% O₂ test versus control. The increase in maximal oxygen consumption and peak ventilation with added dead space and 38% O₂ suggests that maximal exercise in cystic fibrosis is limited by arterial hypoxemia.