Orthopoxvirus is a genus of poxviruses that includes many species isolated from mammals, such as Camelpox virus, Cowpox virus, Ectromelia virus, Monkeypox virus, and Volepox virus, which causes mousepox. The most famous member of the genus is Variola virus, which causes smallpox. It was wiped out using another orthopoxvirus, the Vaccinia virus, as a vaccine.

Some orthopoxviruses have the ability to infect non-host species, such as Monkeypox virus, which is capable of establishing infection in humans. Zoonoses of many of these mammalian isolates have been reported. Others, such as Ectromelia virus, are very specific for their hosts.

Aerosols of concentrated virus may result in orthopox infection, especially in non-immunized individuals. Needle sticks, especially with concentrated virus, may result in severe local infection of the skin even in immunized individuals.

The initial symptoms include fever, malaise, head and body aches, and sometimes vomiting. Lesions that developed into crater-like ulcers surrounded by inflammatory tissue and eventually covered by thick black crusts are the characteristic indicators of orthopox infection. Severe edema and erythema may affect large areas in cases of severe infection. Encephalitis (alteration of mental status and focal neurologic deficits), myelitis (upper- and lower-motor neuron dysfunction, sensory level and bowel and bladder dysfunction), or both may result from Orthopoxvirus infection. Rarely, orthopoxviruses may be detected in cerebrospinal fluid. Some mammalian orthopox infections are known to result in high instances of mortality.