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Objectives Interleukin-37 (IL-37) has been identified as a potent inhibitor of the immune response. This study aimed to examine IL-37 expression in patients with chronic active hepatitis B (CAHB), and explore its possible regulatory role during inflammation. Methods Peripheral blood mononuclear cells (PBMCs) were collected from control (n = 20) and CAHB patients (n = 30) before and after treatment with entecavir (EVT) for 24 weeks. The PBMCs were cultured with lipopolysaccharide and IL-37 expression was determined by real-time polymerase chain reaction and flow cytometry. The mRNA and protein concentrations of IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in PBMCs were also measured. Results Levels of IL-37, IL-1β, IL-6, and TNF-α were significantly increased in the supernatant of PBMCs from patients with CAHB. IL-37 significantly reduced the expression of IL-1β, IL-6, and TNF-α. EVT resulted in regression of intraocular inflammation in patients with CAHB, associated with decreased production of IL-37. Conclusion These results suggest that increased expression of IL-37 was associated with the suppression of the inflammatory response in patients with CAHB. Furthermore, EVT treatment of CAHB was also correlated with downregulation of IL-37, indicating that EVT may partially alleviate the immune response by modulating IL-37 production.