Regeneration of diseased bone is challenging. Guided bone regeneration (GBR) has been applied to favor the bone repair. Photobiomodulation (PBM) is also a recognized therapy able to improve bone repair in healthy and diseased individuals. Thus, with the hypothesis that PBM therapy could improve the GBR of diseased bone, this study evaluated the effect of PBM as adjunctive therapy to GBR in osteoporotic rats. Osteoporosis was induced in rats using the oophorectomy model. Then, 5-mm calvaria bone defects were created and treated according to the experimental groups, as follows: with no further treatment (Control); conventional GBR (Membrane), GBR and PBM applied with 3 s, 4 J/cm and 0.12 J per point (PBM-1) and GBR and PBM applied with 10s, 14 J/cm, 0.4 J per point (PBM-2). PBM therapy (808 nm, 40 mW, 1.42 W/cm) was applied immediately, 48 and 96 h postoperatively. Four and eight weeks later, the samples were harvested and processed for micro-computerized tomography (Micro CT). Data were statistically compared (p < 0.05). From 4 to 8 weeks mostly significant changes were observed in the PBM groups. The bone volume fraction and number of trabeculae of the PBM groups, especially the PBM-1, were significantly higher than those of Control (p < 0.0001). The values of thickness and separation of the trabeculae and structural model index of the PBM groups were significantly smaller than Control (p < 0.0001). The connectivity density was significantly higher on Membrane and PBM groups than Control (p < 0.0004). The application of PBM as adjunctive therapy to GBR results in enhanced bone formation and maturation in comparison to the conventional GBR in the regeneration of lesions of osteoporotic bone in rats. Overviewing the challenges that face bone regeneration in patients with osteoporosis, our findings open new perspectives on the treatment of bone defects under osteoporotic conditions.Copyright © 2020 Elsevier B.V. All rights reserved.