Biventricular pacing (BiV) has been shown to reduce wall stress and workload in regions near the pacing sites. This trial investigated if BiV near the ischemic region would reduce chest pain in patients with refractory angina due to severe coronary artery disease (CAD). Eleven patients were implanted with BiV devices with leads positioned at or adjacent to their ischemic regions as detected by single-photon emission computed tomography (SPECT) and randomized to either pacing turned ON or OFF for 3 months, and then crossed over for 3 months. With pacing turned ON, a Dynamic atrioventricular (AV) delay was set for approximately 90% and 70% of the intrinsic AV delay at the resting heart rate and at the onset of symptoms, respectively. One patient was excluded from the analysis due to a large amount of RV pacing during the OFF periods (24-64%) and due to an inability to properly deliver therapy because of an excessive number of ventricular premature complexes. Overall, with the device ON vs. OFF, the number of angina episodes (0.8 ± 0.4 vs. 1.2 ± 0.7 per week, P = 0.03) and amount of nitroglycerin used (0.2 ± 0.1 vs. 1.0 ± 0.7 per week, P = 0.11) was lower with BiV pacing. Furthermore, the treadmill exercise time to symptoms trended higher (427 ± 65 vs. 408 ± 64 s, P = 0.19), and the sum of fluorodeoxyglucose-positron emission tomography (FDG-PET) scores trended lower (7.9 ± 3.5 vs. 12.0 ± 4.0, P = 0.11) with the device ON vs. OFF. Nevertheless, there were no significant differences in SPECT myocardial perfusion scores, left ventricle ejection fraction, wall motion score index, and quality of life scores with device programmed ON vs. OFF (all P > 0.05). In conclusion, this pilot study demonstrated that BiV-P at or near the ischemic region was feasible and associated with significant reductions in angina in patients with severe CAD. Adequately powered prospective studies are needed to confirm these findings.