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Purpose: To compare the safety and efficacy of 25-gauge pars plana vitrectomy (PPV) with either platelet-rich plasma (PRP) or inverted internal limiting membrane (ILM) flap for the treatment of large macular hole., Methods: Pseudophakic patients with idiopathic macular holes with a minimum diameter (MD) of 600-1500 μm were randomized into two groups (30 patients each): 25-gauge PPV with either inverted ILM flap (group A) or PRP (group B)., Results: Mean MD in groups A and B were 803.33 ± 120.65 μm and 784.73 ± 120.10 μm, respectively (P = 0.552). Mean base diameter in groups A and B was 1395.17 ± 240.57 μm and 1486.90 ± 281.61 μm, respectively (P = 0.180). The median presenting best-corrected visual acuity (BCVA) was logMAR 0.78 (range 0.78-1.00) and logMAR 0.78 (Range 0.60-1.00) in groups A and B, respectively (P = 0.103). Anatomical closure was achieved in 90% (n = 27/30) and 93.3% (n = 28/30) eyes in groups A and B, respectively (P = 0.158). Type 1 closure was achieved in 76.7% (n = 23/30) and 83.3% (n = 25/30) eyes in groups A and B, respectively. Median BCVA at postoperative 3-month in groups A and B was logMAR 0.60 (range 0.48-0.60) and logMAR 0.60 (range 0.48-0.78), respectively (P = 0.312). The average visual improvement was 2.0 and 2.5 early treatment diabetic retinopathy study (ETDRS) lines in groups A and B, respectively (P = 0.339). None of the patients developed postoperative exaggerated inflammatory reactions., Conclusion: Using platelets for the treatment of large macular holes is as safe and effective as an inverted ILM flap., Competing Interests: None