A proposed new small-animal (rodent) model for studying the pathogenesis and treatment of severe orthopoxvirus infections is described. Thirteen-lined ground squirrels (Spermophilus tridecemlineatus) were infected intraperitoneally and intranasally with monkeypox virus (MPXV). A fulminant illness developed in all animals, and they died 6-9 days after infection. Virus was cultured from the blood and oropharynx several days before death; at necropsy, all of the organs tested contained relatively high titers of MPXV. The major pathologic findings were in the liver, which showed centrilobular necrosis, steatosis, and basophilic inclusion bodies in hepatocytes. Splenic necrosis was also observed, as well as interstitial inflammation in the lungs. The pathologic features of MPXV in ground squirrels are similar to that described with MPXV in macaques and severe variola (smallpox) virus infection in humans.