To assess the determinants of bronchopleural fistula (BPF) flow, we used a surgically created BPF to study 15 anesthetized intubated mechanically ventilated New Zealand White rabbits. Mean airway pressure and intrathoracic pressure were evaluated independently. Mean airway pressure was varied (8, 10, or 12 cmH2O) by independent manipulations of either peak inspiratory pressure, positive end-expiratory pressure, or inspiratory time. Intrathoracic pressure was varied from 0 to -40 cmH2O. BPF flow varied directly with mean airway pressure (P < 0.001). However, at constant mean airway pressure, BPF flow was not influenced independently by changes in peak inspiratory pressure, positive end-expiratory pressure, or inspiratory time. Resistance of the BPF increased as intrathoracic pressure became more negative. Despite increased resistance, BPF flow also increased. BPF resistance was constant over the range of mean airway (P < 0.01) pressures investigated. Our data document the influence of mean airway pressure and intrathoracic pressure on BPF flow and suggest that manipulations which reduce transpulmonary pressure will decrease BPF flow.