ObjectiveAdditive manufacturing offers a tailored approach to tissue engineering by providing anatomically precise scaffolds onto which stem cells and growth factors can be supplied. Polyetherketoneketone (PEKK), an ideal candidate biomaterial, is limited by a poor implant–bone interface but can be functionalized with adipose‐derived stem cells (ADSC) to promote integration. This in vivo study examined the interaction of a three‐dimensional printed PEKK/ADSC implant within the critical‐sized mandibular defect in a rabbit model.Study Design/MethodsTrapezoidal porous scaffolds with dimensions of 1.5 × 1.0 × 0.5 cm were printed using selective laser sintering. ADSCs were seeded on the scaffolds that were then implanted in marginal defects created in New Zealand rabbits. Rabbits were euthanized at 10‐ and 20‐week intervals. Microcomputed tomography was used to characterize bone ingrowth and was correlated with histological analysis. Stress testing was performed on the scaffolds before and after implantation.ResultsAll scaffolds were well integrated into adjacent bone. Bone‐to‐tissue volume increased from 30.34% ( ± 12.46) to 61.27% ( ± 8.24), and trabecular thickness increased from 0.178 mm ( ± 0.069) to 0.331 mm ( ± 0.0306) in the 10‐ and 20‐week groups, respectively, compared to no bone regrowth on the control side (P < 0.05). Histology confirmed integration at the bone–implant interface. Biomechanical testing revealed a compressive resistance 15 times that of bone alone (P < 0.05)Conclusion3D‐printed PEKK scaffolds combined with ADSCs present a promising solution to improve the bone–implant interface and increase the resistance to forces of mastication after mandibular reconstruction.Level of EvidenceNA. Laryngoscope, 127:E392–E398, 2017