The effect of chronic phenobarbital administration on the pharmacokinetics of theophylline was studied in 6 healthy, nonsmoking adults. Subject compliance was verified by the determination of plasma phenobarbital levels. Following four weeks of phenobarbital administration, all six subjects showed a resultant increase in serum clearance varying from 11% to 60% with a mean increase of 34% (from 3.01 to 4.04 L/hr/1.73 M2). Theophylline appears to be metabolized more rapidly during chronic phenobarbital administration. This effect, therefore, must be taken into account when administering barbiturates to asthmatic patients for whom theophylline therapy is prescribed.