Brain edema is a critical component of hepatic encephalopathy (HE) associated with acute liver failure and such edema appears to be principally due to astrocyte swelling (cytotoxic edema). Ammonia is believed to represent a major factor responsible for astrocyte swelling, although the mechanisms by which ammonia causes such swelling are not completely understood. Recent studies have implicated potential role of oxidative stress, and the mitochondrial permeability transition (mPT). While it is not known how oxidative stress and the mPT cause astrocyte swelling, it is reasonable to suggest that these events may affect one or more plasma membrane proteins involved in water and ion homeostasis in astrocytes. One such protein strongly implicated in brain edema in other neurological conditions is the water channel protein aquaporin-4 (AQP-4), which is abundantly expressed in astrocytes. This article summarizes the potential role of AQP-4 in brain edema in in vivo models of HE, as well as in ammonia-induced cell swelling in cultured astrocytes. The involvement of AQP-4 in the effects of manganese, another toxin implicated in HE, will also be discussed.