This study seeks to confirm the progressive changes in cardiac output and heart rate previously reported with 8 h exposures to constant hypoxia, and to examine the role of sympathetic mechanisms in generating these changes. Responses of ten subjects to four 8 h protocols were compared: (1) air breathing with placebo; (2) isocapnic hypoxia (end-tidal PO2 = 50 mmHg) with placebo; (3) isocapnic hypoxia with beta-blockade; and (4) air breathing with beta -blockade. Regular measurements of heart rate and cardiac output (using ultrasonography and N2O rebreathing techniques) were made with subjects seated in the upright position. The sensitivity of heart rate to rapid variations in hypoxia (GHR) and heart rate in the absence of hypoxia were measured at times 0, 4 and 8 h. No significant progressive effect of hypoxia on cardiac output was detected. There was a gradual rise in heart rate with hypoxia of 11 ± 2 beats min-1 in the placebo protocol and of 10 ± 2 beats min-1 in the beta-blockade protocol over 8 h, compared to the air breathing protocols. The rise in heart rate was progressive (P < 0.001) and accompanied by progressive increases in both GHR (P < 0.001) and heart rate measured in the absence of hypoxia (P < 0.05). No significant effect of beta-blockade was detected on any of these progressive changes. We conclude that sympathetic mechanisms that act via beta -receptors play little role in the progressive changes in heart rate observed over 8 h of moderate hypoxia. Experimental Physiology (2000) 85.5, 557-565.