SummaryFemale guinea pigs, inoculated intravaginally with a herpes simplex virus‐type 2 (HSV‐2) strain M1, developed typical symptoms of a primary and recurrent genital herpes infection. Sera from HSV‐2 infected guinea pigs taken during the primary or recurrent stages of the genital infection contained complement (C)‐fixing antibody which reacted with an apparent type specificity to an early 4 h HSV‐2 infected cell extract (AG‐4) when compared to a 4 h HSV‐1 infected cell extract. This C‐fixing anti‐AG‐4 activity was shown to be associated with the IgG2 subclass and directed primarily against HSV‐2 infected cell polypeptide (ICP)6 and ICP8. Furthermore, C‐fixing anti‐AG‐4 levels remained constant after the primary infection and during recurrences for over 6 months. Thus, while the anti‐AG‐4 response in guinea pigs was of the IgG type, it varied from that found previously in human genital HSV‐2 sufferers which was of the IgM type. Also, while an IgG anti‐AG‐4 response in human genital HSV‐2 sufferers is associated with a reduction in the number of recurrences, this reduction is not apparent in the guinea pig model.