The aim of this study was to develop a pH-sensitive chitosan/polyvinyl pyrrolidone (PVP) based controlled drug release system for clarithromycin. The hydrogels were synthesized by cross-linking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN). These semi-IPNs were studied for their content uniformity, swelling index (SI), mucoadhesion, wettability, in vitro release and their release kinetics. The hydrogels showed more than 97% content of clarithromycin. These hydrogels showed high swelling and mucoadhesion under acidic conditions. The swelling may be due to the protonation of a primary amino group on chitosan. In acidic condition, chitosan would be ionized, and adhesion could have occurred between the positively charged chitosan and the negatively charged mucus. In the alkaline condition, less swelling and mucoadhesion was noticed. In vitro release study revealed that formulation containing chitosan (2% w/v) and PVP (4% w/v) in the ratio of 21:4 showed complete drug release after 12 h. Release profile showed that all the formulations followed non-Fickian diffusion mechanism. The cross-linking and compatibility of clarithromycin in the formulation was studied by Fourier transform infrared (FTIR) spectroscopic analysis, differential scanning calorimetry (DSC) and powder X-ray diffraction (p-XRD) study, which confirmed proper formation of semi-IPN and stability of clarithromycin in the formulations. The surface morphology of semi-IPN was studied before and after dissolution in simulated gastric fluid (SGF, pH 1.2) which revealed pores formation in membrane after dissolution. The results of study suggest that semi-IPNs of chitosan/PVP are potent candidates for delivery of clarithromycin in acidic environment.