OBJECTIVE : Leukocyte- and platelet-rich fibrin (L-PRF) represents a natural, low-cost product which may promote tissue healing by mechanisms not fully elucidated. Diabetes mellitus (DM) disrupts bone healing by inducing inflammation and oxidative stress (OS), mechanisms regulated by microRNAs (miRs). The aim of the present study was to investigate the microRNA-21 (miR-21) involvement in diabetic bone regeneration using L-PRF alone or in combination with a standard grafting material. METHODS : After the induction of diabetes (alloxan 100 mg/kg), four cranial osteotomies were made in diabetic (n = 12) and non-diabetic (n = 12) rabbits: one was left empty and the remaining three were grafted with L-PRF, bovine hydroxyapatite (Bio-Oss®) and L-PRF + Bio-Oss®. Two and eight weeks postoperatively, the samples were harvested for miR-21 expression (Real-time RT-PCR) and enzyme-linked immunosorbent assay analyses. RESULTS : Diabetic rabbits showed decreased miR-21 and matrix metalloproteinase-9 (MMP-9) protein expression while increased malondialdehyde (MDA) levels two weeks postoperatively; however, there were no significant differences in miR-21 and MMP-9 levels between diabetic and non-diabetic rabbits in samples taken eight weeks postoperatively. Application of L-PRF and L-PRF + Bio-Oss® improved miR-21 and MMP-9 and decreased MDA levels while Bio-Oss® alone enhanced superoxide dismutase (SOD) activity levels in diabetic rabbits. CONCLUSIONS : L-PRF alone or in combination with bovine hydroxyapatite as bone graft could be beneficial in DM since it seems to improve inflammation-modulatory miR-21 expression and decreases oxidative stress.