In this study, carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca2+. The pH-sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions. As a potential protein drug delivery system, the beads were loaded with a model protein (bovine serum albumin, BSA). To improve the entrapment efficiency of BSA, the beads were further coated with a chitosan/CMC polyelectrolyte complex (PEC) membrane by extruding a CMC/BSA solution into a CaCl2/chitosan gelation medium. Finally, the release studies of BSA-loaded beads were conducted. We found that, the maximum swelling ratios of the beads at pH 7.4 (17-21) were much higher than those at pH 1.2 (2-2.5). Higher entrapment efficiency (73.2%) was achieved in the chitosan-coated calcium-CMC beads, compared with that (44.4%) in the bare calcium-CMC beads. The PEC membrane limited the BSA release, while the final disintegration of beads at pH 7.4 still leaded to a full BSA release. Therefore, the chitosan-coated calcium-CMC hydrogel beads with higher entrapment efficiency and proper protein release properties were a promising protein drug carrier for the site-specific release in the intestine. (c) 2006 Wiley Periodicals, Inc.