In this investigation, superporous hydrogels containing poly (acrylic acid-co-acrylamide)/O-carboxymethyl chitosan (O-CMC) fullinterpenetrating polymer networks (SPH-IPNs) were evaluated for their potentials in effective insulin absorption via the oral route. Insulin release from the SPH-IPNs exhibited sensitivity towards pH and ionic strength. After drug loading and release, the circular dichroism (CD) spectra revealed that conformation of insulin had no significant alteration and bioactivity of insulin was well preserved according to hypoglycaemic effect in mice. Through their abilities to bind Ca2+ and to entrap the enzymes, SPH-IPNs could partly inactivate trypsin and-chymotrypsin, and SPH-IPN with higher O-CMC/monomer ratio appeared more potent. Swollen SPH-IPNs could attach mechanically and muco-adhere to the intestinal wall, thus achieving improved retentive properties compared to commonly used muco-adhesive excipient Carbopol? 934. Transport of insulin across rat intestine and colon ex vivo was enhanced around two- to three-fold after application of the SPH-IPN. Insulin-loaded SPH-IPN showed significant hypoglycaemic effects following oral administration to healthy rats, achieving a 4.1% pharmacological availability compared to subcutaneous insulin injection. These pronounced properties demonstrated that the SPH-IPN would be a promising peroral carrier for insulin and other peptide drugs.