In complicated pregnancy, fetal hypoxemia rarely occurs in isolation but is often accompanied by fetal acidemia. There is growing clinical concern on the combined effects on neonatal outcome of fetal hypoxemia with fetal acidemia. However, the effects on the fetal defense responses to acute hypoxemia during fetal acidemia are not well understood. This study tested the hypothesis that fetal acidemia affects the fetal defense responses to acute hypoxemia. The hypothesis was tested by investigating, in the late gestation sheep fetus, surgically prepared for long-term recording, the in vivo effects of acute fetal acidemia on: 1) the fetal cardiovascular responses to acute hypoxemia; and 2) the neural and endocrine mechanisms mediating them. Under general anesthesia, 5 sheep fetuses at 0.8 of gestation were instrumented with catheters and Transonic flow probes around the femoral and umbilical arteries. Five days later, animals were subjected to an acute hypoxemia protocol during I.V. infusion of saline or treatment with acidified saline. Treatment with acidified saline reduced the fetal basal pH from 7.35±0.01 to 7.29±0.01 without alteration of basal cardiovascular variables, blood glucose or plasma concentrations of catecholamines, ACTH and cortisol. During hypoxemia, treatment with acidified saline increased the magnitude of the fetal bradycardia and femoral vasoconstriction, whilst concomitantly increasing chemoreflex function and enhancing the increments in plasma concentrations of catecholamines, ACTH and cortisol. Acidemia also reversed the increase in umbilical vascular conductance during hypoxemia to vasoconstriction. In conclusion, the data support the hypothesis tested and show that acute acidemia markedly alters the fetal hemodynamic, metabolic and endocrine responses to acute hypoxemia.