Thogoto and Dhori viruses are tick-borne orthomyxoviruses infecting humans and livestock in Africa, Asia, and Europe. Here, we show that human MxA protein is an efficient inhibitor of Thogoto virus but is inactive against Dhori virus. When expressed in the cytoplasm of stably transfected cell lines, MxA protein interfered with the accumulation of Thogoto viral RNA and proteins. Likewise, MxA(R645), a mutant MxA protein known to be active against influenza virus but inactive against vesicular stomatitis virus, was equally efficient in blocking Thogoto virus growth. Hence, a common antiviral mechanism that is distinct from the antiviral action against vesicular stomatitis virus may operate against both influenza virus and Thogoto virus. When moved to the nucleus with the help of a foreign nuclear transport signal, MxA(R645) remained active against Thogoto virus, indicating that a nuclear step of virus replication was inhibited. In contrast, Dhori virus was not affected by wild-type or mutant MxA protein, indicating substantial differences between these two tick-transmitted orthomyxoviruses. Human MxB protein had no antiviral activity against either virus.