We reported previously that the administration of anti-α/β murine interferon antibody (anti-IFN-Ab) to C57BL/6J mice genitally infected with herpes simplex virus type 2 (HSV-2) dramatically increases morbidity and mortality. The effect of anti-IFN-Ab is visible early postinfection and it is more evident when low virus doses are used. This report describes our study of the mechanism of action of anti-IFN-Ab. We found that anti-IFN-Ab did not affect peripheral multiplication of the virus at the site of infection. The T-cell cytotoxic activity of spleen and lymph node cells of HSV-2 genitally infected C57BL/6J mice was dependent on the virus dose and peaked 7 days postinfection and, therefore, was excluded as a possible mechanism for the effect of anti-IFN-Ab. Natural killer (NK) cell activity paralleled the effect of anti-IFN-Ab closely; the activity peaked early postinfection, and there was no correlation between NK cell activity and virus dose. We have now observed that in mice treated with anti-IFN-Ab, the NK cell activity was significantly lower than in mice infected and not treated with anti-IFN-Ab. The lack of effect of anti-IFN-Ab on local multiplication of HSV-2 coupled with the decrease in NK cell activity indirectly point to a non-antiviral mechanism of action of endogenous IFN in viv