Adoptive transfer of spleen cells from mice 4 days after infection with herpes simplex virus type 2 (HSV-2) reduced the virus titer in the liver of recipient mice infected 24 h before transfer. Macrophage chemotactic factor (CF) and macrophage migration inhibition factor (MIF) were produced by day 3 of infection in spleen cell cultures stimulated with HSV-2, but not with control antigen, i.e. 1 day before the cells are active in adoptive transfer. Interferon was produced in cultures established throughout the infection but not in normal spleen cells. From days 1 to 5 of infection interferon was produced irrespective of in vitro restimulation, although the highest amounts were always produced after stimulation with the specific antigen. Spleen cells from mice infected for 6 days produced interferon only when stimulated with HSV-2. The cells from 6-day-immune mice active in adoptive transfer and CF and MIF production were found to be Thy 1+, Ig- and Lyt2-. Both Thy 1+ and plastic adherent cells were necessary for interferon production, whereas Ig+ and Lyt2+ cells did not produce interferon. The interferon was acid stable and neutralized by antiserum against alpha/beta-interferon and thus has the characteristics of alpha-interferon. The data indicate that a delayed type hypersensitivity reaction with lymphokine-induced macrophage recruitment into infectious foci may be a central feature of the recovery process in HSV-2-induced hepatitis. A possible role of interferon produced by the accumulated cells needs further investigation.