The clinical, virological and immunocytochemical features of three children who recovered from acute herpes simplex encephalitis (HSE) before the age of 2 years, and who developed secondary severe focal epilepsy after a symptom-free period, leading to neurosurgery 3–10 years later are described. In one child, relapse of HSE occurred immediately after surgery. In all three patients, brain sample biopsies showed abundant CD3-positive T lymphocytes with a majority of CD8 cells, and abundant activated macrophage-microglial cells, a pattern similar to that found in acute HSE. Herpes simplex virus DNA was retrieved from the tissue biopsy in one case. The long-term persistent cerebral inflammatory process observed after HSE differed from that observed in another chronic viral disease, subacute sclerosing panencephalitis. This inflammatory reaction may be a result either of low-grade viral expression or self-induced immune activation. The role of inflammation in triggering epilepsy remains hypothetical. Solving these issues should have major therapeutic implications. Herpes simplex virus DNA latency in brain may be the source of replicative HSE relapse.