To report the long-term outcomes of large diameter epiretinal lyophilized amniotic membranes (lAMs) in recurrent or persistent macular holes (MHs) with or without rhegmatogenous retinal detachment (RRD), in a prospective interventional case series. Ten eyes of 10 patients underwent pars plana vitrectomy for MH-associated RRD (n = 5) or persistent MH without RRD (n = 5), in a university Hospital. A 3 or 4 mm diameter disc of lAM, stained with 0.06% trypan blue, was inserted with a catheter through a sclerotomy and positioned over the MH. Gas or silicone-oil tamponade was used. At 1 year, the main outcome was anatomic success defined as complete MH closure. Secondary outcomes were best corrected visual acuity (BCVA) recovery, changes in ellipsoid zone (EZ) and external limiting membrane (ELM) defects, complications. Mean follow-up was 13.8 ± 2.9 months (range, 12-18). Mean baseline data were minimum and maximum diameters, respectively, 945 ± 330 and 1507 ± 717 μm; axial length 26.58 ± 3.38 mm; and number of prior surgeries 1.4 ± 0.96. At 1 year, anatomic success was achieved in eight eyes (80%), and two had reduced diameter of MH. All RRDs were reattached without recurrence. Mean logMAR BCVA improved from 1.92 ± 0.58 to 1.17 ± 0.57 (p < 0.001), with nine eyes (90%) achieving ≥0.3 logMAR improvement. Mean EZ and ELM defects decreased (p = 0.004, p = 0.003, respectively). Postoperative complications were RRD (n = 1) reattached by subsequent surgery, lAM slightly retracted under silicone (n = 1), foveal atrophy after early lAM displacement (n = 1). A 1-year follow-up highlighted that epiretinal large discs of blue-stained lAM can help safely close refractory MHs, and provide satisfactory visual recovery.