In left bundle branch block (LBBB) thallium-201 myocardial scintigraphy frequently reveals septal abnormalities in the absence of coronary artery disease (CAD) and gives rise to "false-positive" results in patients with suspected CAD. It has not yet been clarified which pathophysiological mechanism is responsible for these perfusion abnormalities. A total of 66 patients with constant LBBB were investigated with 201Tl or technetium-99m-hexakis-methoxyisobutylisonitrile (MIBI), 62 underwent coronary angiography. Of 12 patients without left anterior descending artery (LAD) or right coronary artery (RCA) stenoses, 11 had a reversible septal activity deficit after 201Tl stress injection, whereas 20 of 22 patients without relevant CAD showed a constant stress/rest septal deficit using MIBI. Regarding patients with significant LAD and/or RCA stenoses, both radio-pharmaceuticals almost always showed a "reversible" septal deficit: with 201Tl in 15 of 16 individuals and with MIBI in 14 of 15. In 12 patients 201Tl was reinjected at rest. In those who had LAD or RCA stenoses (n = 5), early septal activity uptake after stress injection was poorer than that after rest injection; in the absence of CAD (n = 7), septal stress uptake corresponded with that of rest injection. It is concluded that septal perfusion abnormalities in LBBB and the absence of CAD are characterized by an exercise-independent reduction of septal blood flow per mass of viable myocardium and that stress/rest injection protocols of myocardial perfusion tracers are able to differentiate between LBBB with and without CAD.