Abstract: Objective To explore the expression levels of interleukin-38 (IL-38) and eosinophils (EOS) in patients with chronic rhinosinusitis (CRS) and their correlation with disease severity. Methods A total of 50 CRS patients who were treated at the Affiliated Hospital of Xuzhou Medical University from May to October 2023 were selected. These patients were divided into two groups: the chronic rhinosinusitis with nasal polyps group (CRSwNP, n=30) and the chronic rhinosinusitis without nasal polyps group (CRSsNP, n=20). Additionally, 20 patients who underwent septoplasty surgery during the same period were selected as controls. All patients underwent nasal sinus CT scans and nasal endoscopy surgery. The IL-38 levels and EOS counts in peripheral blood and local tissue were measured. The differences in IL-38, EOS, and Lund-Mackay CT scores among the groups were compared. According to the Lund-Mackay CT scores, CRS patients were divided into a severe group (score >10) and a mild group (score ≤10), and the levels of IL-38 and EOS were compared between the two groups. The correlation between these levels and CT scores was analyzed. Results The CRSwNP group showed decreased IL-38 levels in peripheral blood and reduced IL-38 in local tissues, compared with the control group and the CRSsNP group (P<0.05). The CRSwNP group also presented increased EOS counts in local tissues and CT scores, compared with the control group and the CRSsNP group (P<0.05). Mild CRS patients had higher expression levels of IL-38 in both peripheral blood and local tissues than severe CRS patients, along with lower EOS counts (P<0.05). The expression levels of IL-38 in peripheral blood and local tissues were negatively correlated with the nasal sinus CT score, while EOS counts in local tissues were positively correlated with CT score (P<0.05). EOS counts in local tissues was negatively correlated with the expression of IL-38 in local tissues (P<0.05). Conclusions IL-38 and EOS are involved in the development of CRS. The expression of IL-38 in peripheral blood and local tissues is negatively correlated with disease severity, while EOS counts in local tissues are positively correlated with disease severity.