Herpes simplex virus (HSV) causes herpes genitalis, primary gingivostomatitis and recurrent herpes labialis. In order to elucidate in vivo mechanisms by which PSK, a biological response modifier, exerts a protective effect against HSV infection, we used an in vitro system to study whether PSK inactivated infectivity of HSV-type 1 (HSV-1) and HSV-type 2 (HSV-2) isolated from patients with herpes genitalis in addition to a laboratory-cultured strain of HSV type 1 (HSV-1-GC+). It was found that HSV-1-GC+ was inactivated by PSK in a dose dependent fashion of concentrations of PSK and virus titers. Concentrations of PSK as low as 0.31 mg/ml was shown to inactivate the infectivity of HSV-1-GC+. Inactivation required at least 30 min of incubation at 37 degrees C with maximal inactivation observed at 60 min incubation time. Similar to HSV-1-GC+, clinically isolated strains of HSV-2 were inactivated by PSK although clinically isolated strains of HSV-1 were resistant to PSK, compared with HSV-2. It was also shown that PSK-treated HSV retained the ability to adsorb to the cell membrane, but did not synthesize viral protein(s). These data illustrate that there is a biological difference in the sensitivity to PSK between HSV type 1 and type 2, and also suggest that PSK could inactivate HSV in lesions at peripheral sites of recurrent herpes.