The effect of short-term exposure of three mouse-strains to simulated high altitude (SHA) of approximately 6,000 m was studied. Subjecting C57BL/6J, DBA/2J or albino mouse strains to SHA for 39 days, occurring on alternating days, increased liver weight in the albino mouse compared to controls. The C57BL strain showed increased growth during SHA compared to other mouse strains. Morbidity score was greater in the albino mouse than in DBA mouse with no death occurring in C57BL mice exposed to SHA. Hepatic alcohol dehydrogenase was induced and mitochondrial aldehyde dehydrogenase was inhibited from corresponding controls subsequent SHA exposure by the C57BL and by the DBA mouse strain, respectively. The onset of ethanol-mediated narcosis was decreased from controls subsequent 21 days of SHA exposure by the DBA and by the albino mouse strain. The central depressant action of ethanol, as measured by the duration of ethanol-narcosis, was decreased in the C57BL mice exposed to SHA for 8, 21, or 35 days compared to controls. No apparent changes occurred in duration of ethanol-narcosis in the other mouse strains. The results suggest strain-difference in response to hypobaric conditions.