Cylindrical hydrogels of hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) as crosslinking agent were prepared by radical polymerization at 70°C. After washing they were soaked in an aqueous drug solution of antipyrine or theophylline. The in vitro drug release experiments were performed in 100 ml isotonic glucose at 37°C. Rectal administration of a hydrogel preparation containing antipyrine was performed in two subjects for 72 h. With a theophylline-containing hydrogel preparation rectal drug administration was performed in six volunteers for 24 h. Plasma and saliva samples were taken regularly and the in vivo drug release was determined by means of a deconuolution procedure. In vitro 1.12g antipyrine had been released according to a matrix-type profile for 72 h, whereas it was calculated that this was 1.13 and 1.09 g in vivo in the two subjects. The release profile in vivo was very similar to that in vitro. The theophylline hydrogel preparation released in vitro a total of 288 ± 6 mg of drug in 24 h and in vivo this amount was calculated to be 288 ± 11 mg (mean ± s.d.). Near-constant plasma theophylline concentrations were obtained after administering the hydrogel preparation. In all six subjects the cumulative drug profile was in almost perfect agreement with that observed in vitro. Hydrogels offer interesting perspectives as rate-controlled rectal drug delivery systems because of the predictable release profile in vivo on the basis of observations in a simple in vitro model.