Septal displacement is postulated as an important mediator of ventricular interdependence. During acute right ventricular loading with the Mueller manoeuvre the septum flattens and shifts leftward. To investigate the mechanism of this septal deformation, we measured transseptal pressures in nine patients during Mueller manoeuvres with simultaneous right and left ventricular micromanometers, and left ventricular configuration with two-dimensional echocardiograms. Data were analysed throughout diastole and at end-systole during control and maximum Mueller manoeuvre (-40 to -80 mmHg airway pressure). Leftward septal displacement during the Mueller manoeuvre was evidenced by an increase in septal radius of curvature at end-diastole persisting through end-systole. The left ventricular free wall radius of curvature was unchanged. During the Mueller manoeuvre, the left ventricular cavity area decreased significantly in the cross-sectional view. All Mueller manoeuvres were associated with a decrease in left-to-right ventricular transseptal pressure gradient throughout diastole. There was no significant change in the gradient at end-systole; septal flattening persisted, however, despite a pronounced left to right pressure gradient. Thus, diastolic septal flattening during right ventricular loading is associated with a decreased transseptal pressure gradient but does not require right ventricular diastolic pressure to exceed left ventricular diastolic pressure. The persistence of flattening in systole suggests that once septal shift occurs during diastole, other forces during systole maintain the deformity despite a large intracavitary transseptal gradient.