The superporous hydrogel containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan (O-CMC) interpenetrating polymer networks (SPH-IPN) that had been developed as an oral delivery vehicle for protein drugs was subject to cytotoxicity and genotoxicity testing, thus evaluating its biological safety in use. In a battery of cytotoxicity assays on RBL-2H3 and Caco-2 cells, the SPH-IPN caused minimal damage towards cell viability, lysosomal activity, and metabolic activity following both direct and indirect treatment. The SPH-IPN did not induce cell apoptosis or DNA breakage in the above cell lines; it did not increase micronucleus (MN) incidence in mouse bone marrow, either. Therefore, the SPH-IPN was preliminarily considered to be biocompatible and might be a safe carrier for protein drugs. In addition, using the HPLC method, residual acrylic acid, acrylamide, and glutaraldehyde in the SPH-IPN were quantified to be 1.4, 2.0, and below 0.2 ppm, respectively. Lack of these low molecular monomers and crosslinker that were mainly responsible for the toxicity provided evidence for the good biocompatibility of the SPH-IPN.