This study was designed to examine the importance of the underlying cardiac pathology on outcome of cardiac resynchronization therapy (CRT), hypothesizing that myocardial infarction scar and other noncontractile segments represent limitations to the ability to resynchronize cardiac contraction in patients with congestive heart failure associated with dilated cardiomyopathy. From October 1999 to April 2002, 158 patients (mean age 65 years, 121 men) were included in a single center, longitudinal, comparative study. All patients had dilated cardiomyopathy and indications for CRT with a mean QRS duration of 174 ms. The patient population was divided into a coronary artery disease (CAD) group that included patients with significant CAD, and no indication, or a contraindication for revascularization, and a non-CAD group that included patients with nonischemic dilated cardiomypopathy. Follow-up data were collected at 3, 6, and 12 months, and yearly thereafter. The median follow-up was 11.2 months. In the CAD group, the LVEF increased from 0.29 to 0.34 (P < 0.0001), the 6-minute walk test distance increased from 310 to 463 m (P < 0.0001), and the percentage of patients in NYHA functional Class III-IV decreased from 83% to 23% (P = 0.04). In the non-CAD group, LVEF increased from 29% to 42% (P < 0.0001), the 6-minute walk test distance increased from 332 to 471 m (P < 0.0001), and the percentage of patients in NYHA functional Class III-IV decreased from 79% to 5%, (P < 0.0001). Comparison of the two groups showed that patients in the non-CAD group had a significantly greater increase in LVEF (P = 0.007) and decrease in NYHA class (P < 0.05). Patients with CAD or non-CAD significantly improved clinically during CRT. Non-CAD patients had a greater increase in LVEF and decrease in NYHA functional class than patients with CAD.