Data regarding factors predicting unfavorable outcomes in adult herpetic meningoencephalitis (HME) cases is scarce in the literature. We conducted a multicenter study to provide insights into the predictors of outcome with special emphasis to use and timing of antivirals. Overall, 501 patients with molecular confirmation from the cerebrospinal fluid were included from 35 referral centers in 10 countries. Overall, 438 patients were found to be eligible for the analysis. Finally, 232 (52.9%) patients experienced unfavorable outcomes; 44 died and 188 survived with sequlae. Age (OR 1.04, 95% CIs 1.02-1.05), Glasgow coma scale (OR 0.84, 95% CIs 0.77-0.93), symptomatic period of 2-7 days (OR 1.80, 95% CIs 1.16-2.79) and over seven days (OR 3.75, 95% CIs 1.72-8.15) until treatment commenced, predicted unfavorable outcomes. The outcome in HME patients is related to a combination of therapeutic and host factors. This study suggests that rapid diagnosis and early administration of antiviral treatment in HME patients are keys to favorable outcome.