Abstract:Background The resurgence of seasonal influenza virus circulation has been seen in 2021–2022 after the temporary suppression in 2020–2021. Neuraminidase inhibitors (NAIs) are widely applied in the clinical treatment of influenza A despite several limitations. Objective To access the efficacy of Xu's influenza decoction (XID) in combination therapy with oseltamivir for the treatment of influenza A. Methods In this retrospective cohort study, the eligible participants were diagnosed with influenza A between June 1, 2018, and May 30, 2022, in the First Affiliated Hospital of Zhejiang Chinese Medical University. According to whether Xu's influenza decoction was applied, patients were divided into two groups: treated with or without XID. Propensity score matching (PSM) was used to further adjust the covariates between groups. The primary outcome was to compare time to defervescence via K-M curves, Breslow tests, and Cox regression analysis. In Cox proportional hazards model, a univariate analysis was performed to obtain preliminary results, while a further multivariate analysis was conducted to study the independent factors that influence defervescence. Subgroup analysis was conducted according to body temperature and time from onset to admission. The secondary outcome consisted of routine blood and C-reactive protein (CRP), length of stay, and medical costs. Results A total of 336 patients with influenza A were enrolled in this study (i.e., 163 patients in the XID+oseltamivir group; 173 patients in the oseltamivir group). After 1:1 matching via PSM, 230 patients meeting the criteria were included in the analysis, with 115 in each arm. The XID+oseltamivir group had shorter time to defervescence (36 h vs 44 h, P = 0.011), shorter length of stay (3 days vs 4 days, P = 0.018), and higher defervescence possibility (HR=1.384, 95%CI: 1.054–1.818). Subgroup analysis indicated that for patients during non-window period (≥ 48 h) with medium-grade fever (38.1℃–39℃), the XID+oseltamivir combination therapy reduced time to defervescence (P = 0.04995/0.004) with a higher defervescence possibility (HR=1.524/1.683). Meanwhile, there's no statistical significance but observable trends of the XID+oseltamivir group in the lower medical costs (3068.07 yuan vs 3120.68 yuan), the lower neutrophils% (48.53% vs 51.00%) and the higher lymphocyte% (39.83% vs 37.72%). Conclusion The combination of XID and oseltamivir can shorten the time to defervescence and length of stay in influenza A. Its antipyretic effect is mainly reflected in the medium-grade and non-window periods.