The influences of genotype and sex on spontaneous motor activity in a Y-maze after nicotine administration and on nicotine concentrations in liver and brain were assessed in three inbred mouse strains. The rank order of liver nicotine elimination rates in these strains was found to be C57 > C3H = DBA for females and DBA > C3H = C57 for males. Within the C57 and C3H strains, females eliminated nicotine significantly faster than males, while DBA females and males eliminated nicotine at similar rates. The rank order of motor depression at early time points after nicotine administration was found to be DBA = C57 > C3H for both males and females. Females of all three strains demonstrated less sensitivity to nicotine's depressant effects than males. There did not appear to be any consistent association between rate of liver nicotine elimination or brain nicotine level and motor depression as measured in the Y-maze. Although variability in liver nicotine elimination and in brain nicotine content may account for some of the observed behavioral effects, these data suggest that strain and sex differences in tissue sensitivity to nicotine are of primary importance.