Both short-term and prolonged treatment with ammonia stimulate Tau efflux from C6 glioma cells, which confirms earlier observations with different CNS preparations. In addition, prolonged, but not short-term treatment reversibly decreases Tau uptake. The results are consistent with in vivo observations showing robust extracellular accumulation of Tau in the CNS under hyperammonemic conditions. Enhancement of Tau efflux by short term ammonia treatment is associated with its passage via a channel (or channels) which in contrast to the release from control cells is (are) not inhibited by NA. However, the increased Tau efflux does not appear to involve active Tau transport. Insensitivity to NA distinguishes ammonia-dependent Tau efflux from C6 cells from that reported in other CNS-derived preparations. Tau release evoked by prolonged ammonia treatment likewise shows a NA-insensitive component, but also a component associated with activation of Tau transport in a reverse mode. Increased outward transport of Tau may be associated with transiently increased expression of TauT mRNA. Mutual relation of the two components, but also the identity of the NA-insensitive efflux route with the anion channels so far described remains to be analyzed.