Guinea pigs were administered antiserum 24 h (As+24) or 72 h (As+72) after intravaginal herpes simplex virus type 2 (HSV-2) challenge. Treatment at either time reduced acute virus replication in the dorsal root ganglia and the overall magnitude of replication in the genital tract. In two studies, As+24 treatment significantly reduced the severity of primary genital skin disease and the frequency of subsequent spontaneous recurrent disease. In contrast, As+72 treatment produced a modest reduction in primary disease severity but did not impact on recurrent disease. Quantitative PCR analysis of dorsal root ganglia DNA from latently infected animals showed that As+24 treatment produced a significantly reduced viral DNA burden, which appeared to correlate with the reduction in recurrent disease. The amount of DNA in the ganglia of As+72-treated animals was not significantly lower than that of controls. These observations have implications for both the dynamics of latency establishment and desirable vaccine characteristics.