The effects of frequency, tidal volume, and inadvertent positive end-expiratory pressure (PEEP) on CO2 elimination were studied in rabbits during high-frequency jet ventilation by measuring CO2 concentration of expired gas using a mass spectrometer. Increasing tidal volume augmented CO2 elimination (P less than 0.01 to 0.001) at each frequency, but when larger tidal volumes were associated with high inadvertent PEEP, CO2 elimination decreased despite the increase in minute ventilation. For constant minute ventilation, CO2 elimination decreased with increasing frequencies. Occurrence of inadvertent PEEP was related to increases in both frequency and tidal volume. If PEEP was controlled, no decrease in CO2 elimination was observed at the larger tidal volume. When PEEP was controlled, changes in tidal volume explained 67.1% to 95.4% of the variance in CO2 elimination not attributable to frequency. Frequency explained very little additional variance (0.1% to 13.8%). CO2 elimination comparable to estimated CO2 production occurred when tidal volumes equal to or smaller than the equipment dead space were used. We conclude that although tidal volume has a greater effect than frequency on CO2 elimination, mechanisms of gas exchange other than bulk gas transport occur during high-frequency jet ventilation.