Objective： To compare the clinical efficacy， changes in immune function， and inflammatory responses in azithromycin combined with cefoperazone-sulbactam in children with severe bacterial pneumonia.Methods： Children with severe bacterial pneumonia admitted in our hospital between April 2023 and March 2025 were retrospectively enrolled. According to the actual treatment regimen， patients were divided into a standard treatment group （azithromycin monotherapy） and a combination therapy group （azithromycin plus cefoperazone-sulbactam）. To control potential confounding bias， propensity score matching （PSM） was performed using age， disease course， and the pneumonia severity index （PSI） score as covariates， with 1∶1 matching. Finally， 41 patients were included in each group. The clinical overall response rate， recovery-related indicators，dynamic changes in immune function and inflammation-related markers before and after treatment， and drug safety were compared between the two groups. Continuous repeated-measures outcomes were analyzed using a 2 （time）×2 （group） repeated-measures analysis of variance.Results： The overall clinical response rate was 97.56% in the combination therapy group and 80.49% in the standard treatment group， indicating superior clinical efficacy of the combination regimen ［relative risk （RR）=1.21， 95% confidence interval （CI）： 1.03-1.43］. Regarding recovery， the durations of major clinical symptoms and length of hospital stay were significantly shorter in the combination therapy group than in the standard treatment group （P<0.05）. Immune function analysis showed that， after treatment， the proportions of CD3⁺ and CD4⁺ cells and the CD4⁺/CD8⁺ ratio increased significantly， while the proportion of CD8⁺ cells decreased significantly in both groups； moreover， the time×group interaction effects were statistically significant （P<0.05）， indicating a greater magnitude of immune improvement in the combination therapy group. In terms of inflammatory and infection-related markers， levels of D-dimer （D-D）， procalcitonin （PCT）， C-reactive protein （CRP）， and soluble intercellular adhesion molecule-1 （sICAM-1） decreased significantly after treatment in both groups， with a more pronounced downward trend in the combination therapy group （P<0.05）. The incidences of adverse reactions were 17.07% and 14.63% in the combination therapy and standard treatment groups， respectively， with no significant difference （P>0.05）.Conclusion： In this real-world retrospective study， compared with azithromycin monotherapy， azithromycin combined with cefoperazone-sulbactam was associated with a higher clinical response rate， faster symptom relief， and more favorable immune modulation and inflammation control in children with severe bacterial pneumonia， without an increased risk of adverse drug reactions. These findings provide real-world evidence supporting the clinical application of this combination regimen and offer a basis for future prospective randomized controlled trials.