Herpes simplex virus type 1 (HSV-1) expresses a receptor that binds the Fc portion of IgG. This HSV-1 Fc gamma-binding protein is, like protein A of Staphylococcus aureus, known to bind human IgG1, IgG2 and IgG4 but not IgG3 subclasses. However, IgG3 with the allotype Gm(s+)(t+), prominent in the Oriental population, reacts with protein A. This prompted us to investigate the reactivity of Oriental IgG3 monoclonal myeloma proteins of various allotypes with the HSV-1 Fc gamma-binding protein. Of seven Oriental IgG3 myeloma proteins with allotypes Gm(s+)(t+)(u-)(b+)(g-), Gm(s-)(t-)(u+)(b+)(g-) and Gm(s-)(t-)(u+)(b-)(g+), all reacted with the HSV-1 Fc gamma-binding protein. This was in contrast to negative reactions obtained with three IgG3 myeloma proteins of Caucasian origin with Gm(b+)(g-) or Gm(b-)(g+) phenotypes. The same binding pattern, i.e. binding of IgG3 of Oriental but not of Caucasian origin, was found with protein A. The binding of the monoclonal Oriental IgG3 proteins was again independent of the G3m phenotype. These findings support the concept that the HSV-1 Fc gamma-binding protein A have a similar binding site on the IgG molecule. All monoclonal IgG3 proteins derived from Oriental subjects with or without histidine at position 435 bound to HSV Fc gamma-binding protein. This suggests that Oriental IgG3 myeloma proteins with Gm(s-)(t-) phenotypes have additional critical amino acid residue substitutions important for HSV Fc gamma binding different from those already known.