Maximum oxygen uptake (V(O2max)) of rats is increased in alkalosis; this increase is larger in hypoxic than in normoxic exercise (Gonzalez et al. (1991b). J. Appl. Physiol., 71:1050-1056). The objective of the present experiments was to determine the mechanism of this phenomenon. NaHCO3 (0.3 M, 9 mmol/kg) was given 15 min before exercise to rats acclimated to PB 380 Torr for 3 weeks (HxBic) and to normoxic rats (NxBic). Additional groups of acclimated and normoxic rats received 0.3 M NaCl (HxNaCl and NxNaCl, respectively). Hx rats exercised at PI(O2) approximately 70 Torr; Nx rats at PI(O2) approximately 140 Torr. V(O2max) was higher after NaHCO3 than after NaCl; this effect was larger in hypoxia. The increase in V(O2max) was mediated through an increased arterio-venous oxygen concentration difference ((Ca - Cv)O2), due, in turn, to a higher Ca(O2) without changes in Cv(O2). (Ca - Cv)O2 after NaHCO3 was larger in hypoxia because a change in pH results in a larger change in HbO2 saturation at the values prevalent in arterial blood of the hypoxic rats (i.e. P(O2) approximately 40-50 Torr, S(O2) 50-60%), than at either the values of normoxic arterial blood or of venous blood during maximum exercise. These results suggest that an increase in hemoglobin-oxygen affinity improves oxygen uptake in the lungs during hypoxia, without hindering its release in the tissues, and therefore has a beneficial effect in hypoxic exercise.