The swelling of a superporous hydrogel containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer networks (SPH-IPN) was sensitive toward the pH, ionic strength, and temperature stimuli. With insulin as a model drug, polymer-protein interaction was detected, and it was physical rather than covalent. Freezing water was the majority of the imbibed water in the swollen SPH-IPNs, and the water-retention ability of the polymer against compression and time of exposure at 37 degrees C was improved as the amount of the O-carboxymethyl chitosan network increased. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay on AD293 and RBL-2H3 cells and an in situ lactate dehydrogenase assay and morphological study on rat intestine confirmed that the SPH-IPNs had satisfactory biocompatibility. These pronounced properties suggested that the SPH-IPNs could be developed as an attractive peroral delivery vehicle for peptide and protein drugs. (C) 2008 Wiley Periodicals, Inc.