Objective This study tested the hypothesis that pregnancy affects the cardiovascular responses to hypoxia by altering the outputs of the peripheral components of the stress system and independent of changes in PaCO2. Design Comparison of cardiovascular and endocrine responses to acute isocapnic hypoxia between pregnant and non-pregnant ewes. Setting Experimental laboratory. Sample Fifteen pregnant (118 days of gestation; term is ca. 145 days) and 8 non-pregnant sheep. Methods Chronically instrumented pregnant and non-pregnant ewes were subjected to 1 hour normoxia, 1 hour of acute systemic isocapnic hypoxia and 1 hour recovery. Main outcome measures Arterial blood pressure, heart rate, femoral blood flow and femoral vascular conductance were recorded continuously throughout and arterial blood samples were taken during normoxia, hypoxia and recovery for the measurement of blood gas, metabolic and endocrine status. Results Basal blood pressure and blood glucose and lactate concentrations were lower in pregnant animals (P < 0.05). In contrast, basal cardiovascular variables and plasma concentrations of noradrenaline, adrenaline, neuropeptide Y, adrenocorticotropic hormone (ACTH) and cortisol were similar in pregnant and non-pregnant ewes. During hypoxia similar reductions in PaO2 occurred in pregnant and non-pregnant animals, without alterations in PaCO2 or pHa. In non-pregnant ewes, acute hypoxia induced a transient increase in arterial pressure and sustained tachycardia without significant changes in femoral haemodynamics. Pregnancy attenuated the cardiovascular response, significantly diminishing the magnitude of the increment in heart rate throughout the hypoxic challenge (P < 0.001). However, hypoxia did not induce significant changes in blood metabolites or in plasma concentrations of any stress hormone measured in either pregnant or non-pregnant animals. Conclusion Pregnancy not only affects basal but also stimulated cardiovascular function in the mother. The diminished chronotropic response to hypoxia in pregnancy is mediated via mechanisms independent of changes in PaCO2 or in plasma concentrations of hormones or metabolites associated with activation of the stress system.