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Introduction Community-acquired pneumonia (CAP) empirical treatments include ceftriaxone and ampicillin-sulbactam (SAM). Their comparative effectiveness in mortality and clinical outcomes remains uncertain. This meta-analysis aimed to compare ceftriaxone with ampicillin-sulbactam in adult patients with CAP, focusing on inpatient mortality, Clostridioides difficile infection, and clinical cure, while accounting for variations in study designs and statistical methodologiesMethods We conducted this study using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed in PubMed/MEDLINE, Embase, Scopus, Cochrane Library, and Web of Science from inception to July 2025. Eligible studies directly compared ceftriaxone and SAM in hospitalized adults with CAP and reported on inpatient mortality, clinical cure, or C. difficile infection. Data extraction and risk of bias assessment were performed independently by two reviewers. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model in Stata.Results Inpatient Mortality: Seven studies totalling 576,989 participants (ceftriaxone: 137,018; SAM: 439,971) showed no significant difference in mortality between groups.Clinical Cure: Two studies (ceftriaxone: 144; SAM: 159) found no significant difference in clinical cure rates (RR = 1.03, 95% CI: 0.86–1.23, p = 0.75; I² = 0%). C. difficile Infection: Pooled analysis found no significant difference between groups (RR = 0.89, 95% CI: 0.47–1.69), with high heterogeneity. Risk of bias across studies ranged from low to some concerns.Abstract #128 Figure 1MortalityConclusion Ceftriaxone does not confer a mortality benefit over ampicillin-sulbactam in the treatment of community-acquired pneumonia. Both agents demonstrated comparable outcomes for mortality, clinical cure, and C. difficile infection. These results should be interpreted cautiously due to methodological sensitivity, heterogeneity, and limited regional representation. High-quality, multicentre randomised controlled trials are needed to confirm these findings in diverse populations. *presenting author