In vivo and in vitro performances of a rectally applied osmotic delivery system containing a water-soluble derivative of theophylline were compared. The system was applied in six healthy volunteers during 72 h, and a comparison was made with two conventional dosage forms, a suppository and a solution administered orally, given once. In vitro, a perfect zero-order release rate with the osmotic system was obtained. In all subjects, application of the osmotic system resulted in a constant steady-state theophylline level just as in a long time zero-order i.v. infusion, which strongly suggests that the release rate in vivo is zero-order too. The release rate was not influenced by renewing the dosage form after 36 hr or by defecation. The in vivo and in vitro release rates were almost identical and subject-independent.