Elevated intracranial pressure (ICP) is strongly aggravating the injury at brain inflammation, resulting in persistent neurological and psychiatric malfunctions. There is no efficient pharmacological treatment to achieve beneficial ICP reduction. Here, the peptide AF-16, comprising the amino terminal part of the endogenous protein Antisecretory Factor (AF), was used to suppress the raised ICP in experimental herpes simplex encephalitis (HSE) in rats. Intranasal instillation of the peptide AF-16 counteracted the ICP elevation and the prevalence of ICP spikes, abrogated the neurological morbidity, and abolished the mortality in a dose-dependent manner. AF-16, 25 microg twice daily intranasally, rescued all animals with HSE and abrogated neurological malfunction. In contrast, only 10% of the rats survived if treated with the vehicle. A single intranasal dose of 25 microg AF-16 to a rat displaying overt HSE symptoms reduced the ICP to normal levels within an hour. No effects on viral replication or antigen distribution were demonstrable. Thus, AF-16 abolished the prevalence of sickness signs, ICP elevation, neurological malfunctions and completely prevented deaths. We advocate use of AF-16 for suppression of elevated ICP.