Twenty-one children with confirmed herpes simplex encephalitis were identified in the California Encephalitis Project.Noteworthy features included 6 (29%) patients with an initial negative herpes simplex virus cerebrospinal fluid polymerase chain reaction test and 13 (62%) patients with extratemporal lobe involvement identified by neuroimaging [corrected]. Eleven cases were <4 years of age, but all 4 fatal cases occurred in adolescents.