Left bundle branch block (LBBB) is a strong predictor of mortality in the presence of coronary artery disease (CAD). Noninvasive evaluation of CAD in these patients has some difficulties. Exercise-induced electrocardiographic ST segment changes are nondiagnostic, and several scintigraphic studies have reported false-positive anteroseptal and septal perfusion defects up to 80%. The authors aimed to assess the diagnostic accuracy of thallium-201 (Tl-201) exercise myocardial single photon emission computerized tomography (SPECT) in comparison with coronary angiography (CAG) for detection of CAD in patients with LBBB. Seventy-seven consecutive patients suffering from chest pain with complete and permanent LBBB were included in the study. All patients (40 women, 37 men, mean age = 54 +/- 7 years) were studied with Tl-201 exercise SPECT and coronary angiography. Tl-201 exercise SPECT for diagnosis of left anterior descending (LAD) artery lesions was interpreted by using three different approaches: method A (conventional approach), method B (involvement of anterior and septal wall regardless of apical wall), and method C (apical approach: involvement of anterior septal and apical wall). Methods A and B gave a sensitivity of 100% each but a specificity of 47% and 56%, respectively. Although method C gave a higher value of specificity than that of methods A and B (98% vs 47% and 56%, respectively p < 0.05), the sensitivity of method C significantly decreased in respect to methods A and B (33% vs 100% p < 0.01). Isolated septal defects were evaluated separately. Isolated septal defects on exercise Tl-201 SPECT were detected in 11 patients, and none of them had CAD according to CAG results. Isolated septal wall involvement had a sensitivity of 0% and a specificity of 74%. The sensitivity and specificity of Tl-201 SPECT for diagnosis of CAD in the right coronary and left circumflex artery territories were 91% and 89%, respectively. In conclusion, the apical approach increased the specificity and decreased the sensitivity of the test. Isolated septal defects seem to have no value for diagnosis of CAD in patients with left bundle branch block.