A series of hybrid nanocomposites containing poly(L-lactide) (PLLA) and polyhedral oligomeric silsesquioxane (POSS) was prepared by solvent casting method for the enhancement of the mechanical properties of PLLA. One of them was mixed by only a physical blending between PLLA and POSS to form PLLA/POSS nanocomposite that did not show considerable improvement. In the other hand, two types of PLLA-POSS additives were synthesized via the ring-opening polymerization of L-lactide in the presence of POSS in different content. On these additives, POSS played as not only an initiator for the ring-opening polymerization reaction due to its hydroxyl functional groups on the surface but also a type of hybrid filler for PLLA/PLLA-POSS nanocomposite after mixing with PLLA matrix. PLLA/PLLA-POSS composite showed significant improvement in mechanical properties because of covalent bonding between PLLA and POSS. In particular, the tensile modulus has been apparently increased in PLLA/5PLLA-5POSS nanocomposites (1,449 MPa) with respect to PLLA control (498 MPa). SEM and XRD data indicated that the dispersion of PLLA-modified POSS was better than that of POSS in PLLA matrix. Although the contact angle was not significantly different, the protein adsorption and platelet adhesion are reduced slightly in PLLA/PLLA-POSS nanocomposite as compared to those of PLLA control and PLLA/POSS. Therefore, it is expected that biodegradable POSS nanocomposite may be helpful to be utilized in biomedical devices such as drug-eluting stents and artificial implants.