It has been proposed that mucoadhesives which adhere to the gastric mucus layer may be used to prolong gastric retention time of oral dosage forms. Preliminary studies, using acrylic hydrogels, have established that the density of carboxyl groups on the polymer chain is important for mucoadhesion. To understand the role(s) of the carboxyl groups in mucoadhesion, acrylic acid-acrylamide random copolymers [P(AA-co-AM)] were synthesized, and the adhesion strength of the cross-linked polymers to the gastric mucus layer was examined as a function of the pH, initial concentration of the cross-linking agent, degree of swelling, and carboxyl-group density. From the study on mucoadhesion of various P(AA-co-AM), it was found that at least 80% of the vinyl groups of the polymer must possess carboxyl groups in the protonated form. The dependence of mucoadhesion on pH and carboxyl-group density suggests that mucoadhesion occurs through hydrogen bonding. In addition, the density of the cross-linking agent significantly affects mucoadhesion. As the density of the cross-linking agent is lowered, the mucoadhesive strength increases, although the density of carboxyl groups in the test surface area is reduced. It is concluded that for mucoadhesion to occur, polymers must have functional groups that are able to form hydrogen bonds above the critical concentration (80% for vinyl polymers), and the polymer chains should be flexible enough to form as many hydrogen bonds as possible.