This study investigated the effects of alkylsulfonated chitosan of different molecular weights on intestinal lipid absorption, blood lipid profiles and circulating adhesion molecules. Syrian hamsters were fed an AIN-93G-based high?fat diet (HFD) and were orally administered 5 or 10 mg/kg BW of oligomer (6 kDa) chitosan (OC), low?molecular-weight (70 kDa) chitosan (LMC) or high?molecular-weight (200 kDa) chitosan (HMC) four times per week for 12 weeks. Animals receiving 2.5 mg/kg BW lovastatin (LOVA) served as a positive control. The blood lipid profiles of these control animals revealed that all chitosans and LOVA significantly decreased total triglyceride, total cholesterol, low?density lipoprotein (LDL)-cholesterol and very?low?density lipoprotein (VLDL)-cholesterol levels in a dose?dependent manner compared to the HFD-fed controls (P<0.05). The blood lipid lowering effectiveness of the three chitosans followed the order of LMC>OC>HMC. Hamsters receiving 5 and 10 mg/kg LMC (P<0.05) exhibited an increase in fecal fat content. Immunoblot assay revealed that acyl?coenzyme A:cholesterol acyltransferase-2 (ACAT-2) expression was suppressed in all chitosan-fed animals compared to the HFD-fed controls (P<0.05). These results suggest that chitosan effectively decreases blood lipid content, and its effectiveness depends on the molecular size of chitosan. The hypolipidemic effect of chitosan is partly attributed to its suppression of intestinal lipid absorption and hepatic ACAT-2 expression.