Both exercise (EIB) and mannitol challenges were performed in asthmatic patients to assess and compare their pulmonary gas exchange responses for an equivalent degree of bronchoconstriction. In 11 subjects with EIB [27 +/- 4 (SD) yr; forced expiratory volume in 1 s (FEV(1)), 86 +/- 8% predicted], ventilation-perfusion (Va/Q) distributions (using multiple inert gas elimination technique) were measured 5, 15, and 45 min after cycling exercise (FEV(1) fall, 35 +/- 12%) and after mannitol (33 +/- 10%), 1 wk apart. Five minutes after EIB, minute ventilation (Ve; by 123 +/- 60%), cardiac output (Qt, by 48 +/- 29%), and oxygen uptake (Vo2; by 54 +/- 25%) increased, whereas arterial Po2 (Pa(O2); by 14 +/- 11 Torr) decreased due to moderate Va/Q imbalance, assessed by increases in dispersions of pulmonary blood flow (log SD(Q); by 0.53 +/- 0.16) and alveolar ventilation (log SD(V); by 0.28 +/- 0.15) (dimensionless) (P < 0.01 each). In contrast, for an equivalent degree of bronchoconstriction and minor increases in Ve, Qt, and Vo2, mannitol decreased Pa(O2) more intensely (by 24 +/- 9 Torr) despite fewer disturbances in log SDQ (by 0.27 +/- 0.12). Notwithstanding, mannitol-induced increase in log SDV at 5 min (by 0.35 +/- 0.15) was similar to that observed during EIB, as was the slow recovery in log SD(V) and high Va/Q ratio areas, at variance with the faster recovery of log SD(Q) and low Va/Q ratio areas. In asthmatic individuals, EIB provokes more Va/Q imbalance but less hypoxemia than mannitol, primarily due to postexercise increases in Ve and Qt benefiting Pa(O2). Va/Q inequalities during both challenges most likely reflect uneven airway narrowing and blood flow redistribution generating distinctive Va/Q patterns, including the development of areas with low and high Va/Q ratios.