We investigated the effects of changes in mean airway pressure (Paw), oscillatory frequency and lung compliance on cardiac output (CO) and pulmonary vascular resistance in seven adult cats (3.0 ± 0.6 kg) during high-frequency oscillatory ventilation (HFOV). The cats were anesthetized with chloralose and urethane and ventilated with a high-frequency oscillator at Paw of 4, 8,12, and 16 cm H20 and frequencies of 3, 6,12,16, and 20 Hz. Saline lavage was used to reduce lung compliance. CO was continuously recorded with an electromagnetic flow probe placed around the aorta and pulmonary vascular resistance was calculated from left atrial and pulmonary artery pressures. Lung lavage reduced static compliance of the respiratory system but did not change CO during pressure-limited ventilation. During HFOV, CO was higher in animals after lung lavage at each Paw. As Paw was raised from 4 to 16 cm H20 during HFOV, CO decreased from 133 ± 36 to 87 ± 31 ml/min kg in animals with normal lungs and decreased from 153 ± 33 to 107 ± 19 ml/min kg after lung lavage (both p < 0.001). Increasing Paw was also associated with an increase in pulmonary vascular resistance both before and after lung lavage (both p < 0.005). Changes in frequency did not significantly alter CO or pulmonary vascular resistance. We conclude that the interaction between the heart and lungs during HFOV is largely mediated by Paw and compliance of the respiratory system. Furthermore, regardless of the degree of lung compliance, cardiac function may be impaired during HFOV as Paw is elevated. © 1988 International Pediatrics Research Foundation, Inc.