The aim of this comparative study was to investigate the in vivo drug release property of hydrophilic dextran tablets with or without swelling in the upper gastrointestinal tract (GIT) in humans. Two kinds of theophylline (TH) tablets were prepared by direct compression from a mixture of carboxymethyldextran and [2-(diethylamino)ethyl]dextran as a matrix capable of forming polyion complex (PIC-tablet), and a mixture of low and medium molecular weight hydroxypropylcellulose as a representative hydrophilic matrix (HPC-tablet). In these tablets, in vitro drug release behaviors and saliva TH level profiles after oral administration to humans were similar to each other, indicating equivalent AUC value. The tablets were then coated with Eudragit® S100, enteric-coating polymer, by a dipping method in order to reveal drug release without full swelling in the upper GIT. Although the two enteric-coated tablets showed a similar in vitro release pattern, saliva level profiles were quite different as reflected in AUC values of 16.4 and 4.68 μg h/ml for enteric-coated PIC- and enteric-coated HPC-tablet, respectively. These results demonstrated that HPC-tablet could not release sufficiently without swelling in the upper GIT. In contrast, enteric-coated PIC-tablet showed an equivalent AUC value to PIC-tablet, indicating that TH was released well even in the lower GIT.