Arg-Gly-Asp (RGD) has been shown to improve cell adhesion to different surfaces through interaction with integrin receptors. Thus, this peptide is widely used to modify different biomaterials suitable for bone tissue engineering ranging from preformed scaffolds to injectable hydrogels. By incorporating RGD to different biomaterials, both in the bulk and on the surface, cell behavior has been modulated to enhance cell-cell and cell-matrix interactions. The presence of RGD on the surface of biomaterials has been demonstrated to not only improve mesemchymal stem cell (MSC) adhesion but also affect their osteoblastic differentiation in a dose-dependent manner when cultured under static conditions. Previous studies have shown that MSC differentiation towards an osteoblastic lineage can be also mechanically up-regulated under conditions of flow perfusion. In this study, we have been able to combine the effects of flow perfusion and RGD-surface modification of poly(L-lactic acid) (PLLA) foams in order to further enhance the osteoblastic differentiation of MSC when compared to the sole effect of surface modification or mechanical stimulation. Modification of PLLA foams with RGD peptides has been previously characterized in our laboratory by soaking the scaffold in an acetone-water mixture, and then incubating in a solution of poly (L-lysine) (polyK). RGDC peptides were linked to the polyK through a disulfide bond, using SPDP as the linker. RGDC surface concentration was varied by changing the polyK incubation concentration. MSC were seeded on the modified scaffolds using oscillating flow perfusion, previously characterized in our laboratory. Long term cultures of MSC were carried out for 4, 8 and 16 days under flow perfusion at different flow rates and RGD surface concentrations. At every RGD surface concentration, the scaffold cellularity and alkaline phosphatase (ALP) activity peaked at day 8, while calcium deposition grew steadily until day 16. MSC osteoblastic differentiation was greatly enhanced at lower RGD surface concentrations. However, the highest RGD surface concentration yielded minimal improvements on the levels of ALP activity and calcium deposition when compared to the controls (plain scaffolds soaked in RGDC and polyK-modified foams). This trend was observed at different flow rates; nonetheless, cell differentiation was more remarkable at higher flow rates. Every flow rate yielded higher levels of differentiation than the static controls.