Cellular and humoral alterations in the cerebrospinal fluid (CSF) of patients with herpes simplex virus (HSV) encephalitis are summarized. At the onset of signs of HSV encephalitis. CSF parameters may appear normal. Lymphoid pleocytosis is usual, and in some cases polymorphonuclear cells may dominate initially. The lymphoid reaction in CSF is prominent for months or even years after infection. Damage to the blood-brain barrier is variable. Total protein level and concentrations of IgG, IgM, and IgA increase in the early phase of the disease. The IgG content usually remains abnormal. Levels of HSV-specific IgG in the CSF increase in correspondence with total IgG content and remain high. A fairly consistent finding is the increased local IgG production in the central nervous system during HSV encephalitis. The ratio of the concentration of HSV antibody in serum to that in CSF is abnormal, usually from the second week of illness. In many cases a fourfold or greater increase in CSF antibody level is observed. The use of enzyme or radioimmunoassay in antibody determinations does not essentially hasten the diagnosis, and isolation of HSV or demonstration of its antigen in brain-biopsy specimens is the only way to achieve a conclusive diagnosis. The persistence of the CSF alterations suggests that HSV encephalitis is a chronic disease.