Objectives: In this study, we aimed to explore the association between the choice of empirical antibiotic therapy and outcomes in ED patients with sepsis. Methods: Patients admitted to ED with sepsis were identified from a single center in the United States, and the data is stored in the MIMIC-IV-ED database. Propensity score matched model was used to match patients receiving empirical mono or combination antibiotic therapy. Logistic regression model was used to assess the associations between empirical antibiotic therapy and in-hospital mortality. Results: A total of 11,380 ED patients with sepsis were included in the data analysis. After PSM, 3920 pairs of patients were matched between the empirical mono-antibiotic therapy group and combination antibiotic therapy group. No significant benefit was observed among the empirical combination antibiotic therapy patients compared with the mono-antibiotic therapy in in-hospital mortality (OR, 0.96; 95 % CI, 0.81-1.15; P: 0.684). Empirical quinolones mono-therapy was associated with significantly lower mortality compared to cephalosporins (OR, 2.12; 95 % CI, 1.35-3.50; P:0.002), penicillins (OR, 1.87; 95 % CI, 1.08-3.34; P:0.029) and vancomycin mono-therapy (OR, 2.15; 95 % CI, 1.19-3.97; P:0.012). Conclusions: Empirical combination antibiotic therapy was not associated with reduced mortality in ED patients with sepsis. Compared with cephalosporins, penicillins and vancomycin, quinolone mono-antibiotic therapy was significantly associated with a decreased risk of in-hospital mortality, especially in patients with respiratory tract infections. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.