In order to obtain a better understanding of intrapulmonary gas mixing and alveolar-capillary gas transport during high frequency oscillatory ventilation (HFO), we measured insoluble gas (He) equilibration, and soluble gas (CO, C2H2) uptake in the lungs of ten anesthetized dogs during closed system HFO (i.e. no fresh gas bias flow). These gases were introduced as a bolus into the lumen of an endotracheal tube and their concentrations were subsequently measured for 20-25 sec from a catheter in the distal end of this tube. Analysis of He concentrations over time was performed using a two compartment series model to calculate a value for effective ventilation (Veff). This Veff was found to range from 0.83 to 23.8 L/min and was directly related to oscillator output (f X VT product, r = 0.77). Analysis of CO and C2H2 concentrations during HFO using a similar two-compartment model having alveolar capillary gas transport in series with Veff allowed for the calculation of pulmonary capillary blood flow (QHFO) and lung diffusing capacity (DHFO). These values for QHFO were found to be not significantly different from simultaneous thermodilution determinations of cardiac output and these values for DHFO were found to be not significantly different from single breath or rebreathing determinations of CO diffusing capacity. Moreover, QHFO and DHFO did not vary with Veff. We conclude that this two compartment in series model is a reasonable way to characterize insoluble and soluble gas behavior during HFO, that Veff is related to oscillator output, and that QHFO and DHFO are not affected by HFO over the range of Veff studied.