This study compared the effects of high frequency oscillatory ventilation (HFOV) and intermittent mandatory ventilation (IMV) on the homeostasis of nitric oxide (NO) in the lower respiratory tract of healthy rabbits. The mechanisms underlying a putative stretch response of NO formation in the airways were further elucidated. Male New Zealand White rabbits were anaesthetized, tracheotomized and ventilated with IMV or HFOV in random order. Total NO excretion increased from 9σ6 ± 0σ8 nl min-1 (mean ± S.E.M.) during IMV to 22σ6 ± 2σ7 nl min-1 during HFOV (P < 0σ001). This increase was not explained by changes of functional residual capacity ([Delta]>FRC). A similar increase in NO excretion during HFOV was seen in isolated buffer-perfused lungs under constant circulatory conditions (P < 0σ05, n = 4). Intratracheal mean CO2 and NO concentrations, measured at 2σ5, 5, 7σ5 and 10 cm below tracheostomy, increased significantly with increasing distance into the lung during both IMV and HFOV (P < 0σ001 for each comparison). At every intratracheal location of the sampling catheter, particularly low in the airways, both CO2 and NO concentrations were significantly higher during HFOV than during IMV (P < 0σ01 for each comparison). We conclude that HFOV increases pulmonary NO production in healthy rabbits. Increased stretch activation of the respiratory system during HFOV is suggested as a possible underlying mechanism. The increase in mean airway NO concentrations may have biological effects in the respiratory tract. Whether it can account for some of the benefits of HFOV treatment needs to be considered.