Hepatitis B virus (HBV) infection is the most critical factor underlying liver cirrhosis and hepatocellular carcinoma worldwide. IL-1β and IL-18, generated by activation of the inflammasome/caspase-1 signaling pathway, play important roles in the control and clearance of HBV. However, the specific relationship between the inflammasome response and IFN-α resistance or viral persistence is yet to be established. Blood samples of patients and supernatant fractions of HBV cell lines were collected for analysis and the effects on inflammasome activation and IL-1β production evaluated via enzyme-linked immunosorbent assay (ELISA), western blot, quantitative RT-PCR and immunofluorescence. IL-1β and IL-18 levels produced in sera of IFN-α non-responders were significantly lower than those of responders and normal donors. Additionally, expression of IL-1β and inflammasome components was decreased in peripheral blood mononuclear cells (PBMC) of non-responders, compared with those of responders. In vitro experiments on HepG2, HepG2.2.15 and HepAD38 cell lines showed that HBV induces a significant decrease in IL-1β production through inhibiting activation of the NF-κB signaling and inflammasome/caspase-1 pathways. And hepatitis B virus polymerase (HBV-Pol) appeared crucial for these inhibitory effects of HBV. IL-1β production is suppressed in HBV carriers and IFN-α non-responders. HBV induces a significant decrease in IL-1β production through inhibiting the NF-κB signaling and inflammasome pathways, for which HBV-Pol is a crucial requirement. Trial approval number: 20 173 402. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.