We report five children who had recurrent central nervous system signs after conventional acyclovir therapy for herpes simplex encephalitis. Secondary exacerbation was characterized clinically by severe ballismic movement disorder in all five children, associated with fever, impairment of consciousness, and seizures. Biologic analysis in all children and magnetic resonance imaging and neuropathology studies of the brain in three cases were compatible with inflammatory reaction. In contrast, all viral cultures remained negative, herpes simplex virus antigen in one child and DNA tested by polymerase chain reaction in four children were undetectable in the first samples of cerebrospinal fluid during the relapse, suggesting a postinfectious, immune-mediated mechanism of relapse in these patients.