In 1981, a localized epizootic of Eastern Equine Encephalitis (EEE) occurred in irrigated areas of four counties in the province of Santiago del Estero, Argentina. The diagnosis was confirmed by serology, and there was no evidence of involvement of Western or Venezuelan equine encephalitis viruses. The overall incidence of equine encephalitis was estimated 17%, the case-fatality rate at 61% and the inapparent: apparent infection ratio less than or equal to 2.9:1. This is the first localized epizootic defined in Argentina and the first in which EEE has been found as the sole etiologic arbovirus. This posed the possibility to look for human infection in the area. In spite of a careful surveillance, no evidence of human disease or infection was found, differing from the situation in USA where EEE virus is a public health problem. Nevertheless vector/s and vertebrate hosts involved in the transmission cycle in Argentina remain unknown, precluding at present speculations on the potential human risk.