The goal of this study was to define the conditions for the fabrication of a bioactive matrix that induces and supports cell proliferation and tissue regeneration. The proposed hypothesis was that a composite graft could be engineered by the absorption of platelet-rich plasma (PRP) onto calcium sulfate (CS). Evaluation of the biological activity of the engineered grafts was based on osteoblast proliferation studies and scanning electron microscopy (SEM) analyses. Graft samples were created in a standard size and shape so that the surface available for attachment and cell proliferation was always identical. Proliferation data were expressed as counts per minute per group and differences among groups were statistically analyzed by analysis of variance followed by the Scheffé test (alpha = 0.1). SEM analysis showed that the combination of CS and PRP presents a preserved crystalline structure well integrated by organic matrix. This combination showed the highest cell proliferation levels (p < 0.001). Further evaluations demonstrated that PRP is activated when combined with CS. When tested as a possible carrier for biologically active molecules such as platelet-derived growth factor (PDGF), CS showed increased cell proliferation (p < 0.001). SEM revealed adherent osteoblasts with broad flattened edges on CS-PRP. This study proposes CS as an efficient carrier for PRP or PDGF and supports the use of these combinations as bioactive matrices in clinical or laboratory applications.