Novel p(HEMA-co-METAC)/alginate semi-interpenetrating hydrogels (semi-IPNs) were developed in the attempt to improve poly(hydroxyethylmethacrylate) biological response, extending its applications in the biomedical field. Materials with different alginate contents were synthesized by copolymerization of 2-hydroxyethylmethacrylate and 2-methacryloxy ethyltrimethyl ammonium chloride monomers in the presence of aqueous solutions of alginate and characterized with respect to p(HEMA-co-METAC) synthesized in the presence of water. Swelling studies in water revealed high values of water uptake (>100%) with marked differences in the swelling degree at increasing polysaccharide content. The effect of ionic strength and of pH on the swelling behavior of hydrogels was also investigated. Higher ionic strengths resulted in a minor swelling degree accordingly with hydrogels polyelectrolyte nature. The introduction of the natural ionizable polysaccharide into the network made the semi-IPNs swelling depending on pH values of the solutions. A biological characterization was performed in terms of protein absorption on hydrogel surfaces, cytotoxicity (ISO 10993-5) and cell adhesion and proliferation studies using both murine 3T3 and human fibroblasts. Hydrogels proved noncytotoxic; moreover, semi-IPN surfaces allowed cell attachment and proliferation, thus supporting their potential biomedical use.