The time course of the effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) systolic function and reverse remodeling is still unknown and was the subject of this study. In particular, whether the acute benefit of CRT translates in late response was explored. Furthermore, the time course of response was compared between ischemic and nonischemic patients. A total of 222 consecutive patients with heart failure (135 ischemic) scheduled for CRT were included. Standard echocardiography was performed before, immediately after CRT, and at 6-month follow-up to measure LV end-systolic volume (ESV), LV end-diastolic volume (EDV), and ejection fraction. Immediately after CRT, significant improvements in LV ejection fraction (from 25 +/- 8% to 31 +/- 9%, p <0.001) and LVESV (from 163 +/- 68 to 149 +/- 63 ml, p <0.001) were observed, followed by an additional improvement at 6-month follow-up (to 34 +/- 9% and 132 +/- 62 ml, respectively, p <0.001 for the 2 comparisons). A significant decrease in LVEDV was observed only at 6-month follow-up (from 217 +/- 73 to 194 +/- 72 ml, p <0.001). An acute decrease in LVESV of 6% could predict response to CRT at 6-month follow-up (defined as a decrease >or=15% in LVESV) with a sensitivity and specificity of 79% and 75%, respectively. The time course of response to CRT was similar in ischemic and nonischemic patients, but decreases in LVESV and LVEDV were significantly greater in nonischemic patients (p <0.001). In conclusion, the beneficial effect of CRT on LV systolic function occurs immediately after CRT, with additional improvement at 6-month follow-up. An acute decrease in LVESV can predict response to CRT at 6-month follow-up. Nonischemic patients show significantly greater LV reverse remodeling compared with ischemic patients.