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Ubiquitin-specific protease 18 (USP18) is a well-established innate immune factor in vertebrates. Although Anatidae birds rarely exhibit distinctive clinical signs during high pathogenicity avian influenza virus (HPAIV) infections, some virus strains cause deadly diseases. Here, we investigated the association between USP18 expression and pathogenicity during HPAIV infections in the Anatidae mallard Anas platyrhynchos. First, mallard USP18 gene (duUSP18) was cloned, and its transcriptional variants, with three different open reading frames, were characterized. Experimental infections with two different pathogenic strains, Miyazaki and Takeo, demonstrated an early induction of duUSP18 mRNA upon HPAIV infection in a bird's whole body in vivo and in primary duck cells in vitro, which was positively associated with pathogenicity in mallards. In addition, duUSP18 knockdown under interferon-β stimulation attenuated viral replication, regardless of pathogenicity. These results indicate a role for duUSP18 in favoring viral replication and virus resistance to type I interferon immunity in mallards., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)