Cardiac resynchronization therapy (CRT) is considered a class I indication in treatment of patients with New York Heart Association (NYHA) functional class III and IV heart failure. However, only small numbers of patients in large clinical trials have been in NYHA functional class IV. Therefore, little is known about the effects of CRT in this group. Therefore, we evaluated the effects of CRT in patients with NYHA functional class IV heart failure. Of all patients referred for CRT implantation, 61 patients with symptoms according to NYHA functional class IV were included. All patients were evaluated before implantation and at 6-month follow-up for clinical changes according to the clinical composite score and changes in left ventricular (LV) volumes and function. In addition, survival was evaluated during long-term follow-up. At 6-month follow-up, 9 patients (15%) had died and 2 patients (3%) were admitted for worsening heart failure. The remaining 39 patients (64%) showed improvement according to the clinical composite score. Decreases in LV end-systolic volume (from 167 ± 88 to 147 ± 93 ml, p = 0.009) and LV end-diastolic volume (from 211 ± 100 to 199 ± 113 ml, p = 0.135) were observed, as was a significant increase in LV ejection fraction (from 22 ± 8% to 28 ± 9%, p <0.001). During a mean follow-up of 30 ± 26 months, 36 patients (59%) died, 27 (75%) from worsening heart failure. Respective 1- and 2-year mortality rates were 25% and 38%. In conclusion, CRT decreases LV volumes and improves cardiac function in patients with NYHA functional class IV heart failure. Nevertheless, (heart failure) mortality remains high in these patients.