C57BL/6 (B6) mice are relatively resistant to infection with herpes simplex virus type 1 (HSV-1). Paradoxically, B6 mice were resistant to 250 ld50 (50% lethal dose) of HSV-l but were killed by 25 or 2.5 ld50 of HSV-l injected intraperitoneally. At the injection site, 250 ld50 of virus induced high titers of interferon (IFN) (> 1,000 international units) that reached maximal levels 2–4 hr after inoculation, whereas 25 or 2.5 ld50 of HSV-l generated only borderline levels of IFN (15–40 international units). Simultaneous inoculation of 250 ld50 of HSV-l and antiserum to mouse IFN (MuIFN) rendered B6mice susceptible to infection; however, treatment with antiserum to MuIFN did not increase susceptibility to 1 ld50 of virus. Injections of MuIFN given 2 hr before and 2 hr after inoculation with virus protected B6 mice against 25 ld50 of virus. Thus, endogenous IFN induced after injection with 250 ld50 of HSV-1 protects B6 mice, whereas lower doses of virus kill the animals because they do not generate a detectable IFN response at the infection site.