The effect of β-blockers in ST-elevation myocardial infarction (STEMI) patients who have undergone primary percutaneous coronary intervention (PCI) has not been adequately evaluated. Using a large multi-center registry in Japan, we identified 3,692 patients who underwent PCI within 24 h from onset of STEMI and were discharged alive from 2005 to 2007. Three-year cardiovascular outcomes were compared between the 2 groups of patients with (N = 1,614) or without (N = 2,078) β-blocker prescription at discharge. Compared with patients in the no-β group, patients in the β group were younger, more frequently male, more often had hypertension and atrial fibrillation but less often had chronic obstructive pulmonary disease than in the no-β group. Statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were more frequently prescribed in the β group. Crude incidence of cardiac death and/or recurrent myocardial infarction (cardiac death/MI) tended to be higher in the β group (7.6 vs. 6.2%, log-rank p = 0.1). After adjusting for potential confounders, β-blockers were associated with significantly higher risk for cardiac death/MI (hazard ratio 1.43, 95% CI: 1.06-1.94, p = 0.01). β-Blocker prescription at discharge was not associated with better cardiovascular outcomes in patients who underwent PCI after STEMI. Large-scale randomized controlled trials are needed to evaluate the role of β-blocker therapy in these patients.