The prognostic effect of beta-blocker treatment on ST-elevation acute myocardial infarction (STEMI) is controversially discussed in the era of reperfusion therapy. From the German multicenter registry Maximal Individual Therapy of Acute Myocardial Infarction PLUS (MITRA PLUS), 17,809 consecutive patients with STEMI treated with a guideline-recommended therapy with aspirin and an angiotensin-converting enzyme inhibitor were investigated; the prognostic effect of additional acute beta-blocker treatment was analyzed. Patients with cardiogenic shock were excluded. Of included patients, 77.6% received additional acute beta-blocker treatment and 22.4% did not. Patients with beta-blocker treatment were younger and more often received reperfusion therapy. Acute beta-blocker treatment was associated with a lower hospital mortality (univariate analysis 4.9% vs 10.8%, p <0.001; multivariate analysis odds ratio [OR] 0.70, 95% confidence interval [CI] 0.61 to 0.81). Acute beta blockade was significantly associated with a lower hospital mortality in patients without (OR 0.66, 95% CI 0.56 to 0.79) and with (OR 0.76, 95% CI 0.60 to 0.98) reperfusion therapy. The greatest benefit of acute beta-blocker treatment, measured by the number needed to treat to save 1 life, was found in patients with anterior MI, a heart rate > or =80 beats/min, no reperfusion therapy, female gender, and age > or =65 years. In conclusion, acute beta-blocker therapy in the clinical practice of treating patients with STEMI, in addition to aspirin and angiotensin-converting enzyme inhibitor therapy, was independently associated with a significant decrease in hospital mortality in patients with and without reperfusion therapy. High-risk patients with STEMI, such as elderly patients and patients without reperfusion therapy, showed a greater benefit of acute beta-blocker therapy than low-risk patients with STEMI.