The purpose of this study was to determine the effect of imposed external resistance on the ventilatory response to He-O(2) breathing during peak exercise. To accomplish this purpose, separate inspiratory and expiratory external resistances were applied to offset for the decrease in intrapulmonary airway resistance with He-O(2) breathing. Seven men and three women (69+/-3 years, mean+/-S.D.) with normal pulmonary function performed graded cycle ergometry to exhaustion breathing room air, He-O(2) (79% He, 21% O(2)), He-O(2) with imposed expiratory resistance, and He-O(2) with imposed inspiratory resistance. Ventilation (VE), lung mechanics, and PET(CO(2)) were measured during each 1 min increment in work rate and were analyzed by one-way ANOVA for repeated measures at rest, ventilatory threshold (VTh), and peak exercise. In response, VE was increased and PET(CO(2)) was decreased at VTh (P<0.01) and peak exercise (P<0.01) whenever breathing He-O(2). Thus, VE was increased during exercise above VTh with He-O(2) breathing regardless of increases in inspiratory or expiratory external resistance. In conclusion, these data suggest that inspiratory resistive unloading is no more important than expiratory resistive unloading to the increase in VE with He-O(2) breathing during heavy and peak exercise.