We determined the relationships among gas exchange, breathing mechanics, and airway inflammation during exercise of moderate through maximum intensities in the asthmatic. Twenty-one habitually active [maximal oxygen uptake (VO_2max), 48.2 ± 7.0 ml^.kg^-1.min^-1], mildto- moderate asthmatics (forced expiratory volume in 1.0 s, 94 ± 13% predicted) performed treadmill exercise to exhaustion (11.2 ± .15 min) at ~90% VO_2max. Arterial O₂ saturation decreased to 94% during the exercise in 8/21 subjects, due in large part to a decreased arterial PO₂ [(PaO₂) 93.0 ± 7.7 to 79.7 ± 4.0 Torr]. A widened alveolar-to-arterial PO₂ difference (AaDO₂) and the magnitude of the ventilatory response contributed approximately equally to the decrease in PaO₂ during exercise. Airflow limitation and airway inflammation at baseline did not correlate with exercise gas exchange, but an exercise-induced increase in sputum histamine levels correlated with the exercise PaO₂ (negatively) and AaDO₂ (positively). Mean pulmonary resistance was high during exercise (3.4 ± 1.2 cmH₂O^.L^{-1 .}s^-1) and did not increase over the timecourse of exercise. Expiratory flow-limitation occurred in 19/21 subjects, averaging 43 ± 35% of tidal volume near end exercise, and end expiratory lung volume (EELV) rose progressively to 0.25 ± 0.47 L greater than resting EELV at exhaustion. These mechanical constraints to ventilation contributed to a heterogeneous and frequently insufficient ventilatory response; arterial PCO₂ ranged from 30 to 47 Torr at end exercise. Thus, pulmonary gas exchange is impaired during high intensity exercise in a significant number of habitually active asthmatic subjects due to high airways resistance and possibly to a deleterious effect of exercise-induced airway inflammation on gas exchange efficiency.