Cardiac resynchronization therapy (CRT) can improve cardiac function in heart failure without increasing myocardial oxygen consumption. However, CRT optimization based on hemodynamics or echocardiography is difficult. QRS duration (QRSd) is a possible alternative optimization parameter. Accordingly, we assessed QRSd optimization of CRT during cardiac surgery. We hypothesized that QRSd shortening during changes in interventricular pacing delay (VVD) would increase cardiac output (CO). Seven patients undergoing coronary artery bypass, aortic or mitral valve surgery with left ventricular (LV) ejection fraction < or =40%, and QRSd > or =100 msec were studied. CRT was implemented at epicardial pacing sites in the left and right ventricle and right atrium during VVD variation after cardiopulmonary bypass. QRSd was correlated with CO from an electromagnetic aortic flow probe. Both positive and negative correlations were observed. Correlation coefficients ranged from 0.70 to -0.74 during VVD testing. Clear minima in QRSd were observed in four patients and were within 40 msec of maximum CO in two. We conclude that QRSd is not useful for routine optimization of VVD after cardiac surgery but may be useful in selected patients. Decreasing QRSd is associated with decreasing CO in some patients, suggesting that CRT can affect determinants of QRSd and ventricular function independently.