The serological response to the ICP-35 group of herpes simplex virus type 2 (HSV-2) proteins was examined 30 d after vaginal challenge with HSV-2 of guinea pigs previously immunized with HSV glycoproteins. Detection of antibodies to ICP-35 proteins correlated best with the magnitude of vaginal viral replication. Animals that developed antibody to ICP-35 proteins had more-frequent recurrences (P <.0002) that were of longer duration (P <.005) than animals that did not. By covariate analysis the number of recurrences appeared to be related to the severity of the acute disease, inversely related to the enzyme-linked immunosorbent assay titer of antibody to HSV glycoproteins, and related to the detection of antibody to ICP-35 proteins. The duration of recurrent disease, however, could only be correlated with the presence of antibody to ICP-35 proteins. Detection of antibody to ICP-35 proteins is thus a useful prognostic indicator for identifying animals that developed more-severe recurrent disease. © 1988 by The University of Chicago.