Background <p>The β-receptor blocker is used to treat heart failure (HF), and its role in the occurrence of atrial fibrillation (AF) is unclear in patients with HF. This study aimed to investigate the relationship between β-receptor blocker use and AF in patients with HF.</p> Methods <p>All data was collected from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The relationship between β-receptor blocker and AF was analyzed by univariate logistic regression, multivariate logistic regression, and subgroup analysis. The machine learning algorithm including logistic and Random forest was used to analyze the importance of variables in AF. The interaction analysis was conducted to determine whether other factors influence the relationship between β-receptor blocker and AF.</p> Results <p>A total of 953 participants were involved. We found that the use of beta-blockers increased the risk of AF this result was not affected by confounding factors (OR (95%CI): 2.821[2.014,3.951], <i>p</i> &lt; 0.01). The interaction analysis showed that myocardial infarction (MI) and β-receptor blocker had an interaction on AF (p for interaction &lt; 0.001). The results of additive and multiplicative interaction analysis indicated that β-receptor-blocker use and infarction are antagonistic in the development of AF in patients with HF ((S (95% CI): 0.283[0.142, 0.563]; AP (95% CI): -1.187[-2.020, -0.354]; RERI (95% CI): -2.237[-3.722, -0.752], OR (95% CI):0.374[0.184, 0.772]).</p> Conclusion <p>This study found that β-receptor blocker use was an important risk factor for AF in patients with HF. β-receptor blocker use was antagonistic to MI in AF in patients with HF.</p> Clinical trial <p>Not applicable.</p>