Background: The positive effect of leukocyte- and platelet-rich fibrin (L-PRF) on osteogenesis has been widely described in vitro. However, clinical and preclinical studies are very little and controversial in demonstrating a significant beneficial effect of L-PRF in bone regeneration. Purpose: The goal of the present study was to compare the potential effect of L-PRF in a standardized model. Materials and Methods: A total of 72 hemispheres were implanted on the calvaria of 18 rabbits and filled with three different space fillers: L-PRF, bovine hydroxyapatite (BHA), BHA+L-PRF, and an empty hemisphere was used as control. Six rabbits were sacrificed at three distinct time points: 1 week, 5 weeks, and 12 weeks. Histological and histomorphometrical analyses were carried out. Results: At the early phase of bone regeneration (1 week), from a descriptive analysis, a higher proportion of connective tissue colonized the regeneration chamber in the two groups containing BHA particles. Nevertheless, no statistical differences were found within the four groups in terms of bone quantity and quality at each timepoint (p=.3623). Conclusions: According to the present study, L-PRF does not seem to provide any additional effect on the kinetics, quality, and quantity of bone in the present model of guided bone regeneration.