Objectives. The aim of this study was to determine the independent hemodynamic effects of an irregular sequence of ventricular cycle lengths in patients with atrial fibrillation (AF). Background. Atrial fibrillation may reduce cardiac output by several possible mechanisms, including loss of the atrial contribution to left ventricular filling, valvular regurgitation, increased ventricular rate or irregular RR intervals. This study was designed to evaluate the effects of an irregular RR interval, independent of the average ventricular rate, on cardiac hemodynamic data during AF. Methods. Sixteen patients with AF were studied invasively. During intrinsically conducted AF (mean rate 102 ± 22 beats/min), the right ventricular apex electrogram was recorded onto frequency-modulated (FM) tape. After atrioventricular node ablation, the right ventricular apex was stimulated in three pacing modes in randomized sequence: 1) VVI at 60 beats/min; 2) VVI at the same average rate as during intrinsically conducted AF (102 ± 22 beats/min); and 3) during VVT pacing in which the pacemaker was triggered by playback of the FM tape recording of the right ventricular apex electrogram previously recorded during intrinsically conducted AF (VVT 102 ± 22 beats/min). Results. Compared with VVI pacing at the same average rate, an irregular sequence of RR intervals decreased cardiac output (4.4 ± 1.6 vs. 5.2 ± 2.4 liters/min, p < 0.01), increased pulmonary capillary wedge pressure (17 ± 7 vs. 14 ± 6 mm Hg, p < 0.002) and increased right atrial pressure (10 ± 6 vs. 8 ± 4 mm Hg, p < 0.05). Conclusions. An irregular sequence of RR intervals produces adverse hemodynamic consequences that are independent of heart rate.