We examined the relationship between the pressure-time product (Pdt) of the inspiratory muscles and the O2 cost of breathing (VO2 resp) in five normal subjects breathing through an external inspiratory resistance with a tidal volume of 800 ml at a constant end-expiratory lung volume [functional residual capacity, (FRC)]. Each subject performed 30-40 runs, each of approximately 30 breaths, with inspiratory flow rates ranging from 0.26 +/- 0.01 to 0.89 +/- 0.04 l/s (means +/- SE) and inspiratory mouth pressures ranging from 10 +/- 1 to 68 +/- 4% of the maximum inspiratory pressure at FRC. In all subjects VO2 resp was linearly related to Pdt when mean inspiratory flow (VI) was constant, but the slope of this relationship increased with increasing VI. Therefore, Pdt is an accurate index of VO2 resp only when VI is constant. There was a linear relationship between the VO2 resp and the work rate across the external resistance (W) for all runs in each subject over the range of W 10 +/- 1 to 137 +/- 21 J/min. Thus, at a constant tidal volume the VO2 resp was related to the mean inspiratory pressure, independent of flow or inspiratory duration. If the VO2 resp were determined mainly during inspiration, then for a given rate of external work or O2 consumption, VI would be inversely related to mean inspiratory pressure. Efficiency (E) was 2.1 +/- 0.2% and constant over a large range of VI, pressure, work rate, or resistance and was not altered by the presence of a potentially fatiguing load. The constant E over such a wide range of conditions implies a complex integration of the recruitment, mechanical function, and energy consumption of the muscles utilized in breathing.