Hemagglutination-inhibiting (HI) antibody to VE virus was found in 0.26 to 0.32 of sera from persons residing at endemic sites in southeastern Mexico (Sontecomapan and Minatitlan, Veracruz). Prevalences of HI antibody were low (0.02) at Lake Catemaco villages (near Sontecomapan but at higher altitude) and on the Pacific side of the Isthmus of Tehuantepec opposite Minatitlan. Many sera (0.65) with HI antibody (titers ≧10) had detectable complement-fixing antibody (titers ≧4), and most sera (0.87) without detectable HI antibody had no detectable neutralizing (N) antibody to VE virus with heated serum diluted 1:4, although in undiluted, unheated serum, N substances suggesting falsely positive results were found in 0.70. Four cases of disease were identified as being caused by Mexican strains of VE virus, three naturally-acquired (two moderately severe and one encephalitic and fatal) and one acquired by aerosol exposure in the laboratory. All but the fatal case were diagnosed by isolation of virus from blood (and a throat swab of one case) and by rises in titers of VE virus antibodies in serum. Although the two moderately severe, naturally-acquired cases occurred in field workers at Sontecomapan and Minatitlan, nine other susceptible field workers did not become infected, presumably at least in part due to exposure only to daytime-biting mosquitoes, and use of protective clothing and repellants.