Six patients with chronic respiratory failure received mechanical ventilation with tidal volumes less than or equal to the dead-space volume, at frequencies of 30 to 900 breaths per minute. The rate of elimination of carbon dioxide from the ventilator system during a brief trial of high-frequency ventilation accurately predicted the long-term effectiveness of a given combination of frequency and tidal volume. Below frequencies of about 200 breaths per minute, the volume of carbon dioxide eliminated from these patients was most strongly related to the product of frequency and tidal volume; at higher frequencies, carbon dioxide elimination was determined by the tidal volume and was independent of frequency. These results suggest that although the effectiveness of high-frequency ventilation is primarily a function of the product of tidal volume and frequency, above a critical frequency the mechanical characteristics of the lung reduce gas transport by limiting the volume transmitted to the periphery of the lung.