Abstract: Objective: To explore the intervention effect of chlorogenic acid(CRA) combined with voriconazole(VRC) on invasive pulmonary aspergillosis in vivo and its immune mechanism. Methods: The rats were divided into normal control group, model group, CRA group, VRC group, and combined treatment group(CRA + VRC group). After the successful establishment of the rat model of invasive pulmonary aspergillosis, the normal control group and the model group were treated with normal saline, and the other groups were given CRA alone, VRC alone and combination of the two drugs for 7 days. The general condition of rats was observed to evaluate the severity of systemic infection. The fungal load in lung tissue and galactomannan(GM) content in alveolar lavage fluid were measured. Hematoxylin-eosin(HE)staining and periodic acid-silver methenamine(PASM) staining were used to observe the pathological changes of lung infection. The protein expression levels of CD68, inducible nitric oxide synthase(iNOS) and Arginase 1(Arg-1) were detected by immunohistochemistry. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of M1 phenotype cytokines tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) and M2 phenotype cytokines IL-10 of macrophages in lung tissue homogenate. Results: Compared with the model group, the CRA+VRC group had the best general condition, and the trend of weight loss was significantly slowed down(P<0.05), and the fungal load and GM concentration in alveolar lavage fluid were significantly reduced(P<0.01). The pulmonary vessels and bronchus of the lung tissue of rats in the model group were obviously invaded by fungi, a large number of mycelia and spores grew, and there was extensive inflammation and hemorrhage, while in the lung tissue of rats in the CRA+VRC group, mycelia was significantly reduced and the damage was light. Compared with the model group, the expression levels of CD68 and Arg-1 protein in the lung tissue of rats in the CRA+VRC group were significantly decreased(P<0.01), and the expression level of iNOS protein was significantly increased(P<0.05). The levels of TNF-α and IL-6 in lung tissue were significantly increased(P<0.05, P<0.01). Conclusion: CRA combined with VRC has a synergistic therapeutic effect on invasive pulmonary aspergillosis model rats, and its mechanism may be related to CRA promoting the phenotype polarization of macrophage M1.