The hypolipidemic activities of high and low molecular weights of chitosan nanopowders (HMW-chitosan-NP: 315kDa; LMW-chitosan-NP: 51kDa) prepared by ultrafine milling were evaluated in rats. The results showed that the hypolipidemic activity of chitosan nanopowder was better than ordinary chitosan, and LMW-chitosan-NP was superior to HMW-chitosan-NP in hypolipidimic activity. Compared with ordinary chitosan, chitosan nanopowder increased the fecal lipids and the activities of serum and liver lipoprotein lipase (LPL) and hepatic lipase (HL) of rats. Rats receiving LMW-chitosan-NP excreted less lipids in feces, but showed higher serum and liver LPL and HL activities compared with those fed HMW-chitosan-NP. These results suggested that compared with ordinary chitosan, the increased hypolipidemic activity of chitosan nanopowder might be attributed to its ability on increasing fecal lipid excretions and stimulating LPL and HL activities, and the better stimulation of LMW-chitosan-NP in activities of these lipases might help it to exceed HMW-chitosan-NP in hypolipidemic activity.