To provide an overview of the use of autogenous platelet concentrates (APCs) in periodontal regeneration and to conduct a systematic review (SR) of the treatment outcomes of periodontal intrabony defects by using platelet-rich fibrin (PRF) compared with other commonly utilized modalities. The eligibility criteria comprised randomized controlled trials (RCTs) comparing the clinical outcomes of PRF with that of other modalities. Studies were classified into 21 categories and into five different groups as follows: Group I (1) open flap debridement (OFD) alone versus OFD/PRF, (2) OFD versus Titanium-PRF (T-PRF) Group II, (3) Comparative PRF protocols (PRF vs. T-PRF), Group III (Comparative Studies to PRF): (4) OFD/PRP versus OFD/PRF, (5) OFD/bone graft(BG)/PRGF versus OFD/BG/PRF, (6) OFD/EMD versus OFD/PRF, (7) OFD/BG/EMD versus OFD/BG/PRF, (8) OFD/collagen membrane (CM) versus OFD/PRF, (9) OFD/BG/BM versus OFD/BG/PRF, (10) OFD/BG versus OFD/PRF, Group IV (Addition of PRF to treatment groups) (11) OFD/BG versus OFD/BG/PRF, (12) OFD/GTR versus OFD/GTR + PRF (13) OFD/EMD versus OFD/EMD/PRF (14) OFD/BG/BM versus OFD/BG/BM/PRF, Group V (Addition of Biomaterial/Biomolecule to PRF): OFD/PRF versus … (15) OFD/PRF/BG, (16) OFD/PRF/antibiotic, (17) OFD/PRF/Metformin, (18) OFD/PRF/Bisphosphonates, (19) OFD/PRF/Statins, (20) OFD/BG/PRF versus OFD/BG/PRF/Statins, and (21) OFD/PRF/low-level laser therapy (LLLT). Weighted means and forest plots were calculated for probing pocket depth (PPD), clinical attachment level (CAL), and radiographic bone fill (RBF). From 596 records identified, 55 RCTs were included. Group I: The use of OFD/PRF statistically significantly reduced PPD and improved CAL and RBF when compared to OFD. Group II: A significant difference between various PRF protocols was only observed for PPD. Group III: No significant advantage was found when comparing OFD/PRF to the following groups: OFD/PRP, OFD/EMD, OFD/BM, or OFD/BG. Group IV: The addition of PRF to OFD/BG led to significant improvements in PPD, CAL and RBF compared with OFD/BG alone. Group V: The addition of either a BG as well as three of the following biomolecules (metformin, bisphosphonates, and statins) to OFD/PRF led to statistically significant improvements in PPD, CAL, and/or RBF when compared to OFD/PRF alone. The use of PRF significantly improved clinical outcomes in intrabony defects when compared to OFD alone. Similar results were observed when OFD/PRF was compared with OFD/BG, OFD/EMD, OFD/PRP, and OFD/BM. The addition of PRF to a bone grafting material as well as the addition of various small biomolecules to PRF may offer additional clinical advantages, thus warranting further investigations. Future research investigating various protocols of PRF, longer-term outcomes, as well as PRF at the human histological level remains needed.