OBJECTIVE: To characterize differences between Herpes Simplex Virus and Varicella-Zoster Virus encephalitis (HSVE and VZVE) and other aetiologies of infectious encephalitis (IE), and to investigate the impact of time-to-aciclovir (ACV) start, ACV dose and duration on outcome. METHODS: We compared 132 HSVE, 65 VZVE, and 297 others IE enrolled in a prospective cohort (ENCEIF). We estimated associations between time-to-ACV start, dose or duration and outcome through adjusted odds-ratio (aOR) using logistic regression analysis. RESULTS: Prevalence of immunodepression differed among aetiologies: 15/65 (23%) for VZVE, 13/132 (10%) for HSVE and 30/297 (10%) for others IE (P