The long-sleep (LS) and short-sleep (SS) lines of mice have been selected for a difference in duration of ethanol-induced sleep time. In our previous study, recent generations of the two lines were found to exhibit differential hypnotic and hypothermic responses to pentobarbital which appear to be explained by differences in elimination. Casual observation that the LS mice were fatter than the SS suggested that this discrepancy may influence the responses of these animals to sedative-hypnotic drugs which differ in lipid solubility. The present study was designed to determine whether the LS and SS mice differ in hypnotic and hypothermic responses to two barbiturates which differ in lipid solubility; to the highly lipid soluble tertiary alcohol, ethchlorvynol; and to the water soluble depressant, methyprylon. Mice of the SS line were more responsive to the lipid soluble depressants than were LS mice, and increasing the lipid solubility of the barbiturates resulted in a greater difference between the lines. LS mice were more responsive to the water soluble depressant, apparently due to differential central nervous system sensitivity rather than to differences in elimination. The whole-body lipid content of the LS mice is double that of the SS mice. The influence of body lipid content on drug disposition may accentuate the elimination differences that result in the lesser responsivity of LS mice to barbiturates and possibly ethchlorvynol. This study indicates that sedative-hypnotic drugs of varying lipid solubilities may not share common mechanisms of action.