This survival study was designed to address whether beta-1-blockade utilizing metoprolol CR/XL (controlled release/extended release) once daily added to standard therapy reduces mortality and morbidity in patients with decreased ejection fraction and symptoms of heart failure. Enrolled in a double-blind randomized study were 3991 patients with chronic heart failure in NYHA functional class II-IV and ejection fraction < or = 0.40 stabilized on optimal standard therapy. Randomization was preceded by a 2-week single blind placebo run-in period. The study medication was uptitrated during 8 weeks starting with 12.5 mg (NYHA functional class III-IV) or 25 mg once daily (NYHA functional class II). The target dose was 200 mg once daily. The primary endpoints were all-cause mortality and combined all-cause mortality and hospitalization (time to first event) and other objectives were cause-specific data on hospitalization, NYHA functional class and quality of life. Mean follow-up time was 1 year. All-cause mortality was reduced in the metoprolol CR/XL group compared with the placebo group, 145 versus 217 deaths, 7.2% per patient year of follow-up versus 11.0% with a relative risk of 0.66 (95% CI 0.53-0.81, nominal p = 0.00009, p adjusted for interim analysis = 0.0062). This effect was consistent across all predefined subgroups. Sudden deaths were fewer in the metoprolol group (79 versus 132 deaths), RR 0.59 (p = 0.0002). Also deaths from worsening heart failure were fewer in the metoprolol group (30 versus 58 deaths), RR 0.51 (p = 0.0023). The combined endpoint total mortality or all-cause hospitalizations was also reduced by metoprolol (641 versus 767 events), RR 0.81 (p = 0.00012). Total mortality or hospitalizations due to worsening heart failure was also reduced (311 versus 439 events), RR 0.69 (p < 0.00001). The number of hospitalizations due to worsening heart failure (317 versus 451, p < 0.00001) and days in hospital due to worsening heart failure (3401 versus 5303 days, p < 0.00001) were also reduced by metoprolol. There was also an improvement in NYHA functional class, assessed by the physicians as well as the McMaster Overall Treatment Evaluation questionnaire (OTE), assessed by the patients (p = 0.028 and p = 0.089, respectively). Permanent early discontinuation was 13.9% in the metoprolol group and 15.3% in the placebo group (RR = 0.90). In conclusion, in patients with symptomatic heart failure metoprolol CR/XL once daily improved survival by 34%, sudden death by 41%, and deaths from worsening of heart failure by 49%. In addition to improvement of survival there was also a reduced need of hospitalizations for worsening heart failure and an improved NYHA functional class and of quality of life assessed in a substudy. Metoprolol was well tolerated with no difference in early discontinuation rate from placebo treatment.