Abstract: Objective To investigate the effects of imipenem combined with linezolid on serum levels of annexin A1 (ANXA1), interferon regulatory factor 5 (IRF5), and heparin-binding protein (HBP) in patients with aspiration pneumonia. Methods A retrospective analysis was conducted on 270 patients with aspiration pneumonia admitted to the Second People's Hospital of Hengshui from March 2023 to March 2025. Based on their medication regimens, patients were divided into a control group (n=135) and an intervention group (n=135). The control group received intravenous imipenem, while the intervention group received intravenous infusion of linezolid in addition to the imipenem regimen. Both groups were treated for 14 days. The two groups were compared in terms of therapeutic efficacy, white blood cell count (WBC), procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ANXA1, IRF5, and HBP levels, as well as adverse reactions. Pearson correlation analysis was used to assess the correlations of ANXA1, IRF5, and HBP with WBC, PCT, CRP, IL-6, and TNF-α. Results The total effective rate in the intervention group was significantly higher than that in the control group (P＜0.05). After 7 and 14 days of treatment, the levels of WBC, PCT, CRP, IL-6, TNF- α, IRF5, and HBP in both groups were significantly lower than those before treatment, while ANXA1 levels were significantly higher (P＜0.05). Furthermore, the levels of these indicators at 14 days of treatment were superior to those at 7 days in both groups (P＜0.05). At both 7 and 14 days of treatment, the intervention group showed significantly lower levels of WBC, PCT, CRP, IL-6, TNF-α, IRF5, and HBP, and significantly higher ANXA1 levels compared to the control group (P＜0.05). No statistically significant difference was observed in adverse reactions between the two groups (P＞0.05). Pearson correlation analysis revealed that ANXA1 was negatively correlated with WBC, PCT, CRP, IL-6, and TNF- α, whereas IRF5 and HBP were positively correlated with these inflammatory markers (P＜0.05). Conclusion The combination of imipenem and linezolid demonstrates significant efficacy in treating patients with aspiration pneumonia, markedly alleviating the inflammatory response, increasing ANXA1 levels, and decreasing IRF5 and HBP levels, and ANXA1, IRF5, and HBP are closely related to the inflammatory response.