Purpose: Irradiation results in deleterious effects on bone healing and integration of titanium implants. The impact of irradiation on osseointegration has been demonstrated in histologic studies, but the underlying molecular mechanisms have not been explored. This study aimed to investigate the effects of single-dose irradiation on the expression of biologic mediators crucial for inflammation, bone formation, and bone remodeling and to relate these molecular activities to implant stability after a 5-week healing period. Materials and Methods: A rat tibia model was used. An external single-dose irradiation of 20 Gy was administered to one leg while the second leg was used as a control. After 8 weeks, the irradiated and non-irradiated tibiae received titanium implants. Five weeks following implantation, implant stability was evaluated by removal torque measurement. Then, the implant and the bone surrounding the implant were retrieved for gene expression analysis of the implant-adherent cells and peri-implant bone, respectively. Results: Irradiation resulted in 55% reduction in removal torque. The implant-adherent cells in irradiated sites revealed downregulation of genes related to bone formation (ALP and OC) and upregulation of proinflammatory (TNF-α) and pro-fibrogenic (PDGF-b) genes. Conversely, the peri-implant bone in irradiated sites revealed upregulation of bone formation and bone remodeling genes. Removal torque showed a negative correlation with pro-inflammatory activity and a positive correlation with osteoblastic activity in the implantadherent cells. Conclusion: The impact of high (20 Gy) single-dose irradiation on osseointegration involves a reduction in bone formation activity and upregulation of pro-inflammatory and pro-fibrogenic activities in the implant-adherent cells. It is also suggested that this single-dose irradiation elicits a different molecular pattern at a distance from the implant surface, characterized by increased bone formation and remodeling activities in the peri-implant bone. Schlagwörter: bone, gene expression, in vivo, irradiation, osseointegration, removal torque