Based on our discoveries of a unique, synergistic interplay between vascular endothelial growth factor (VEGF) and specific domains of the matrix protein fibronectin (FN), we used recombinant technology to create a new protein construct derived from the cell-binding and VEGF-binding domains of FN. We wished to test the hypothesis that this prototype recombinant FN (rFN) protein would enhance cellular and capillary ingrowth in vivo into expanded polytetrafluoroethylene (ePTFE) implants. ePTFE disks of high porosity (60 micron internodal distance) were embedded with fibrin gel and heparin, with/without mixtures of VEGF and rFN and were implanted subcutaneously in rats. Control implants embedded with fibrin glue and heparin alone showed an average of 8.5% (±0.51% standard error mean (SEM)) cellular ingrowth. The addition of either VEGF or rFN caused a modest but significant increase in cellular ingrowth (12.7 ± 1% and 11.8 ± 0.98%, respectively, p < 0.004). However, the combination of rFN/VEGF/heparin dramatically increased cellular ingrowth (27.6 ± 1.62%, p < 0.001), compared with all other treatments. Quantification of capillary ingrowth yielded the same pattern. These results suggest that the incorporation of such biological modulators into cardiovascular implants could offer new strategies for the design of a ready-made small diameter prosthetic graft with enhanced capacity for neovascularization and endothelialization.