This report describes a new therapeutic approach to the treatment of adults with portal systemic encephalopathy using sodium benzoate and sodium phenylacetate, two compounds that increase conjugated nitrogen excretion in the urine and that have been shown to be an effective treatment for children with congenital hyperammonemia. The study was a double-blind cross-over study in which each patient was his own control. All patients either improved their mental status (six of eight) or maintained a mental status comparable to that achieved with conventional therapy [lactulose or neomycin (two of eight)]. All decreased their blood ammonias on these medications and seven of eight improved their portal systemic encephalopathy index. It is suggested that these medications may be useful in the treatment of portal systemic encephalopathy.