The elimination of ethanol following the intravenous and intraperitoneal administration of five ethanol doses was measured in two mouse lines, the long-sleep (LS) and short-sleep (SS), that differ markedly in central nervous system sensitivity to ethanol. Both dose and route of administration affected the relative ethanol elimination in these two mouse lines. When the ethanol was given i.v., a steady increase in elimination rate was seen in the SS mice as the dose was increased. In the LS mice, consistent changes in rate with dose were not seen. At the lower doses tested, the LS eliminated ethanol more rapidly than did the SS but at higher doses the mouse lines did not differ. When the ethanol was given i.p., increases in rate with dose were not seen. Rather, the SS elimination rate remained constant as the dose was increased, whereas in the LS a decrease in rate was observed. As a consequence, the SS eliminated ethanol more rapidly than did the LS at higher doses. A potential explanation for these results is that ethanol elimination, following the administration of large doses, is affected by both enzymological factors and central nervous system sensitivity to ethanol. The central nervous system factors may be mediated via ethanol-induced hypothermia.