To optimize the properties of chitosan-coated liposomes for oral administration of peptide drugs, we examined the effect of type of chitosan and the structure of liposomal systems on the mucoadhesiveness of liposomes and resultant pharmacological effects of the liposomal peptide drug. A low-molecular weight chitosan (LCS) and a high-molecular weight chitosan (CS) were used as coating polymers of liposomes containing elcatonin (eCT). The muco-penetrative behaviors across the mucous gel layer covering the intestinal epithelial cells and the pharmacological effect after intragastric administration were determined in rats. The results showed that both LCS-coated liposomes (LCS-Lips) and CS-coated liposomes (CS-Lips) could permeate the mucous layer in the small intestine. The most interesting result was that LCS-Lips containing eCT showed remarkably more prolonged effectiveness in decreasing the blood calcium concentration than did CS-Lips containing eCT, moreover, it was also found that LCS had more efficiency to protect eCT from the enzymatic degradation than CS. In comparing the area above the plasma calcium concentration time curves (AAC) values among eCT-containing liposomes with different structures, i.e. eCT adsorbed on coated liposomes (eCT-ad-CS-Lip, eCT-ad-LCS-Lips) and eCT encapsulated in coated liposomes (eCT-encap-CS-Lips, eCT-encap-LCS-Lips), eCT-encap-CS-Lip showed much higher effectiveness than eCT-ad-CS-Lip. However, the AAC value for eCT-ad-LCS-Lip was comparable to that for eCT-encap-CS-Lip, while the value for eCT-ad-CS-Lip was nearly zero. These results suggested that LCS is a good mucoadhesive polymer candidate for enhancing the bioavailability of orally administered peptide containing liposomes, while encapsulation of eCT within the liposomal particles is important to protect eCT against enzymatic degradation in the gastrointestinal (GI) tract.