Quantitative virus and interferon titers were assayed in temporal lobe brain biopsy specimens (six patients); in various regions of the brain at autopsy (five of the six patients); and in serums and CSF during courses of herpes simplex virus, type 1 (HSV-1) encephalitis. Until the tenth day of neurologic disease, interferon (geometric mean titer, 25 units/mL) was present in each virus-positive brain biopsy specimen. The geometric mean HSV-1 titer at brain biopsy was 328 tissue culture dose (TCD)50/g. On the sixth day of disease, CSF from the sole survivor contained 160 units/mL, but five other samples of CSF contained no detectable interferon. No serums from any of the six patients contained interferon. At autopsies performed on the sixth to 19th day of neurologic disease, 13 of 35 of the regional areas of the brain retained HSV, but only a single specimen from a temporal lobe had measurable interferon. Early in the course of HSV-1 encephalitis, substantial interferon titers are present in areas of virus multiplication. This local brain interferon is insufficient alone to inhibit progression of a disease but could possibly be important in combination with antiviral chemotherapy.