Rats, with and without bile duct ligation (BDL), were injected with hexobarbital (i.p. and i.v.) and blood concentrations measured as a function of time. Analysis of these curves using a single-compartment model showed that BDL altered hexobarbital pharmacokinetics in a manner dependent upon the duration of BDL and the route of administration of hexobarbital. Clearance from the blood and the rate constant for elimination (K) were reduced after 72 h BDL but not after 12 h BDL. The absorption of hexobarbital after i.p. injection was slowed by 12 and 72 h BDL. Seventy-two hour BDL also increased the volume of distribution of hexobarbital but only when the drug was administered i.p. Previously reported data are supported showing impairment of hepatic microsomal drug metabolism after 72 h BDL, but not after 12 h BDL. Earlier speculations were confirmed that BDL decreased the absorption of i.p. administered hexobarbital, although this does not appear to be a significant factor in prolonging hexobarbital sleeping time.