Viruses of the Bunyaviridae family cause a variety of diseases ranging from uncomplicated fever to potentially lethal encephalitis and hemorrhagic fever. Little is known about the factors determining pathogenicity in the vertebrate host. Interferons have been reported to be inhibitory, but their mode of action against members of the Bunyaviridae has not yet been elucidated. The interferon-induced MxA protein encoded on human chromosome 21 is a large GTPase with antiviral activity against distinct negative-strand RNA viruses, notably influenza viruses. Here we show that MxA inhibits representative members of the Bunyaviridae family by interacting with an early step of virus replication. When constitutively expressed in stably transfected Vero cells, MxA prevented the accumulation of viral transcripts and proteins of Hantaan virus (genus Hantavirus). Other members of the family such as La Crosse virus (genus Bunyavirus) and Rift Valley fever virus and sandfly fever virus (both genus Phlebovirus) were likewise inhibited, and virus titers were reduced up to 10(4)-fold. Our data indicate that humans have evolved a mechanism of controlling these viruses irrespective of differences in viral coding strategies.