In 2003, US officials identified several human monkeypox cases and traced the virus exposure to infected captive prairie dogs. The virus was likely introduced through a shipment of imported African rodents, which were kept with other mammals, including prairie dogs, in a pet distribution facility in the Midwest. To prevent the further introduction and spread of the virus, federal agencies restricted the importation of African rodents and restricted the domestic trade or movement of prairie dogs and certain other rodents. In this qualitative assessment of the risk for monkeypox associated with the 2003 outbreak, we conclude that the probability of further human infection is low; the risk is further mitigated by rodent import restrictions. Were this zoonotic disease to become established domestically, the public health effects could be substantial.