Cellular response to our designed biodegradable polyrotaxanes was evaluated in terms of physicochemical interaction with plasma membrane and intracellular metabolism of platelets. The polyrotaxanes, in which many hydroxypropylated (HP-) alpha-cyclodextrins are threaded onto a poly(ethylene glycol) chain capped with a L-phenylalanine moiety via a peptide linkage, were synthesized and characterized. The polyrotaxanes inhibited cytoplasmic calcium increase in platelets, increased plasma membrane fluidity of red blood cell ghosts, and elevated cytoplasmic cyclic-3',5'-AMP levels in platelets. Such cellular response to the polyrotaxanes was observed, which was more than that to constituent molecules. These results suggest that the supramolecular structure of the polyrotaxanes contributes to acceleration of the physicochemical interaction with plasma membrane and intracellular metabolism of platelets. Thus, biodegradable polyrotaxanes can be useful as new biomaterials for fabricating blood-contacting devices.