<p>Patients diagnosed with acute cholecystitis or cholangitis admitted to three tertiary Grade A hospitals between January 2022 and March 2026 were enrolled. All subjects were divided into the cefoperazone-sulbactam group and piperacillin-tazobactam group according to the initial empirical antimicrobial regimens. Relevant clinical data were collected and statistically analyzed using SPSS 27.0 software, including clinical effective rate, mortality rate, 30-day readmission rate, bacterial clearance rate and safety profiles and so on between the two groups. To compare the clinical efficacy and safety of cefoperazone-sulbactam versus piperacillin-tazobactam in the empirical treatment of acute biliary tract infections under real-world clinical conditions via a multicenter retrospective study. A total of 147 patients with acute biliary tract infections were finally enrolled, including 78 cases in the cefoperazone-sulbactam group and 69 cases in the piperacillin-tazobactam group. No significant differences were observed in baseline characteristics between the two groups (<i>P</i> &gt; 0.05). The overall clinical effective rate was slightly higher in the cefoperazone-sulbactam group than that in the piperacillin-tazobactam group (92.31% vs. 82.61%, <i>P</i> = 0.073). Multivariate Logistic regression analysis revealed that initial empirical treatment with cefoperazone-sulbactam was associated with better clinical outcomes compared with piperacillin-tazobactam (<i>P</i> = 0.039, OR = 3.129, 95% CI : 1.058–9.257), and higher baseline body temperature before treatment was significantly associated with an increased risk of poor clinical outcomes (<i>P</i> = 0.018, OR = 3.558, 95% CI : 1.247–10.150). There were no statistical differences in all-cause mortality, 30-day readmission rate, antimicrobial regimen escalation rate, post-treatment ICU admission rate, 7-day and 14-day bacterial clearance rates as well as length of hospital stay between the two groups (<i>P</i> &gt; 0.05). In terms of safety, the total incidence of adverse reactions in the cefoperazone-sulbactam group was significantly higher than that in the piperacillin-tazobactam group (25.64% vs. 11.59%, <i>P</i> = 0.030), mainly manifested as a higher incidence of coagulation disorders (8.97% vs. 0, <i>P</i> = 0.015). No significant differences were found in liver and renal dysfunction, pancytopenia and other adverse events between the two groups. Our retrospective analysis with a limited sample suggested that cefoperazone-sulbactam may confer comparatively favorable clinical efficacy for empirical management of acute biliary tract infections relative to piperacillin-tazobactam, though the crude between-group difference in overall clinical effective rate failed to reach statistical significance. Meanwhile, cefoperazone-sulbactam presents obvious safety disadvantages, especially the higher risk of coagulation dysfunction. No significant differences were found between the both agents in other clinical outcomes. Further multicenter, large-sample randomized controlled trials are required to fully verify the clinical efficacy and safety of these two agents for acute biliary tract infections.</p>