The clinical and serological outcome of genital herpes simplex virus type 2 (HSV-2) inoculation in animals previously orally infected with HSV type 1 was evaluated. A prior HSV-1 oral infection modified the genital HSV-2 infection so that only four of 18 (22%) animals were initially symptomatic although all but one animal shed HSV-2 from the cervicovaginal area for at least 5 days following inoculation. Three of four animals with symptomatic initial disease also developed recurrences, as did an additional six animals that did not manifest acute genital disease. Anti-glycoprotein gG-1 antibody was found in 17 of 18 animals with only an HSV-1 infection and anti-gG-2 antibody in all of nine animals with only an HSV-2 infection. Anti-gG-2 antibody was detected in eight of 17 animals with a prior HSV-1 infection following HSV-2 inoculation and one had an indeterminate response. Eight of these nine animals developed recurrent genital disease compared to one of eight that did not respond to gG-2 (P less than 0.006). Thus a prior oral HSV-1 infection modified both the initial presentation of HSV-2 infection and the HSV type-specific serological response.