The MX dynamin-like GTPase 1 (Mx1) gene has been shown to confer strong resistance to influenza A virus infections in mice. Most laboratory mouse strains carry nonsense or deletion mutations in Mx1 and thus a non-functional allele whereas wild-derived mouse strains carry a wild type Mx1 allele. Congenic C57BL/6J (B6-Mx1r/r) mice expressing a wild type allele from the A2G mouse strain are highly resistant to influenza A infections, to both mono- and poly-basic subtypes. Furthermore, in genetic mapping studies, Mx1 was identified as the major resistance locus to influenza infections. Here, we investigated if the Mx1 protective function may be influenced by genetic background. We generated a congenic mouse strain carrying the A2G wild type Mx1 resistance allele on the DBA/2J background (D2-Mx1r/r). Most remarkably, congenic D2-Mx1r/r mice expressing a functional Mx1 wild type allele are still highly susceptible to H1N1 virus.