Objective To investigate the efficacy of 3D-printed individualized titanium mesh ( 3D-PITM) combined with guided bone regeneration (GBR) in a rabbit model of osteoradionecrosis of the jaws (ORNJ) with bone defects. Methods Eighteen white rabbits with ORNJ-induced bone defects were divided randomly into three groups:a group (debridement and suturing for natural healing), b group (debridement and conventional GBR), and c group (debridement and 3D-PITM-supported GBR). Two rabbits from each group were euthanized at 4, 8, and 12 weeks,respectively. Bone defect repair was evaluated by immunohistochemical staining to detect expression levels of the osteogenesis-related factors alkaline phosphatase ( ALP ), osteocalcin ( OC), and bone morphogenetic protein-2 (BMP-2), and the inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Results There was no significant difference in ALP expression among the groups at 4 weeks, but OC levels were lower in c group than in b group. At 8 and 12 weeks, however, ALP, BMP-2, and OC expression levels were all significantly higher in c group than in a and b groups. Expression levels of IL-6 and TNF-α were significantly lower in c group than in Groups a and b at 4, 8, and 12 weeks, but there was no significant difference in IL-6 expression levels between groups b and c at 4 weeks. Conclusions The combination of 3D-PITM and GBR demonstrated significantly superior bone defect repair efficacy in ORNJ compared with conventional GBR or natural healing alone.