This study was undertaken to determine if patients who lack muscle phosphorylase (i.e., McArdle's disease), and therefore the ability to produce lactic acid during exercise, demonstrate a normal hyperventilatory response during progressive incremental exercise. As expected these patients did not increase their blood lactate above resting levels, whereas the blood lactate levels of normal subjects increased 8- to 10-fold during maximal exercise. The venous pH of the normal subjects decreased markedly during exercise that resulted in hyperventilation. The patients demonstrated a distinct increase in ventilation with respect to O2 consumption similar to that seen in normal individuals during submaximal exercise. However their hyperventilation resulted in an increase in pH because there was no underlying metabolic acidosis. End-tidal partial pressures of O2 and CO2 also reflected a distinct hyperventilation in both groups at approximately 70-85% maximal O2 consumption. These data show that hyperventilation occurs during intense exercise, even when there is no increase in plasma [H+]. Since arterial CO2 levels were decreasing and O2 levels were increasing during the hyperventilation, it is possible that nonhumoral stimuli originating in the active muscles or in the brain elicit the hyperventilation observed during intense exercise.