A classical antiviral response was induced in the upper and lower trachea of pigs upon infection with both swH1N1 and huH1N1 compared to mock inoculated control pigs, primarily through activation of several ISGs and interferon stimulated proteins in the upper (OASL, MX1, IFIT3, and ISG15) and lower trachea (OASL, MX1, MX2, ISG15, IFIT3, IFI6, RSAD2, OAS1, IFIT1, ISG12(A), BST2, IFI44, XAF1, and RTP4). Here, OAS1 is linked to infection.