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Bone grafting materials may enhance tissue regeneration after endodontic, periodontal, or implant surgery. The differences in physical and biological properties between products may result in different osteoblastic responses. This study was designed to determine whether interleukin-1β and Tgf-β1 production by primary cultures of rat osteoblasts differed when cells were exposed to three grafting materials: BioOss, OsteoGraf N-300, and PepGen P-15. Cells were exposed to materials for 24, 48, and 72 h and were characterized by mineralized nodule formation. Supernatants were collected for Lowry and enzyme-linked immunosorbent assays to assess cytokine production. All groups produced mineralized nodules after 14 days. Statistical analysis revealed no difference in interleukin-1β production between groups, but a significant increase in Tgf-β1 production was noted in the PepGen P-15 group. These results indicate that PepGen P-15 stimulates osteoblasts to express Tgf-β1, which may accelerate repair of bone defects created during periradicular or dental implant surgeries.