To assess whether genetic factor(s) determine liver triglyceride (TG) levels, a 10- mouse-strain survey of liver TG contents was performed. Hepatic TG contents were highest in BALB/cByJ, medium in C57BL/6J, and lowest in SWR/J in both genders. Ninety and 76% of variance in hepatic TG, in males and females respectively, was due to strain [genetic]-effects. To understand the physiologic/biochemical bases for differences in hepatic TG among the three strains, studies were performed in males of the BALB/cByJ, C57BL/6J, and SWR/J strains. In vivo hepatic fatty acid (FA) synthesis rates and hepatic TG secretion rates ranked BALB/cByJ~C57BL/6J>SWR/J. Hepatic 1- ¹⁴C-palmitate oxidation rates and plasma -hydroxybutyrate concentrations ranked in reverse order: SWR/J>BALB/cByJ~C57BL/6J. After 14 hours of fasting, plasma FFA and hepatic TG contents rose most in BALB/cByJ and least in SWR/J. - hydroxybutyrate concentrations rose least in BALB/cByJ and most in SWR/J. Adaptation to fasting was most effective in SWR/J and least in BALB/cByJ, perhaps because BALB/cByJ are known to be deficient in SCAD, a short-chain fatty acid oxidizing enzyme. To assess the role of insulin action, glucose tolerance test (GTT) was performed. GTT-glucose levels ranked C57BL/6J>BALB/cByJ~SWR/J. Thus, strain-dependent [genetic] factors play a major role in setting hepatic TG levels in mice. Processes such as fatty acid production and hepatic export in VLDL on the one hand, and fatty acid oxidation on the other, explain some of the strain-related differences in hepatic TG contents. Additional factor(s) in the development of fatty liver in BALB/cByJ remains to be demonstrated.