The effect of pretreatment with probenecid (200 mg/kg, i.p.) on the sensitivity of the central nervous system (CNS) to thiopental and hexobarbital was investigated with an EEG-threshold method. The threshold dose was significantly decreased by pretreatment with probenecid for thiopental but not for hexobarbital. This was due to an increased penetration of thiopental into the CNS, but for hexobarbital an increase in penetration could also be demonstrated by analysis of brain and serum concentrations after infusion of an equal dose of barbiturate. The concentrations in brain at the EEG-threshold were not influenced by pretreatment with probenecid for either of these barbiturates, which shows that there was no synergism between these barbiturates and probenecid due to the depressant effect of probenecid on the CNS.