Phenobarbital and diphenylhydantoin were measured concurrently in cerebral tissue and plasma during neurosurgical therapy of focal epilepsy. A significant correlation was found between brain and plasma phenobarbital levels. The mean brain: plasma phenobarbital ratio in ten patients was 0.91 ± 0.08 (SEM). The frequency of cortical spike discharges following drug withdrawal was independent of the brain phenobarbital concentration. A single patient taking diphenylhydantoin alone had a ratio of 1.5 which agreed with the value of 1.3 observed in a nonsurgical patient studied post mortem. White matter contained approximately twice as much diphenylhydantoin as gray matter. A significant correlation was also observed between brain and plasma levels of these drugs in the rat. Hence, drug levels in plasma can serve as an indicator of their concentration in brain.