| Summary: | <i>Background and Objectives:</i> To compare the long-term toxicity of infracyanine green (IFCG) to brilliant blue G (BBG) in inverted internal limiting membrane flap surgery (I-ILMFS) for large, full-thickness macular holes (FTMHs). <i>Materials and Methods:</i> Prospective randomized study including 39 eyes with ≥ 400 µm idiopathic FTMH who underwent I-ILMFS with either IFCG or BBG. Postoperative 6- and 12-month corrected distance visual acuity (CDVA), closure rate, and swept-source optical coherence tomography parameters, including ellipsoid zone (EZ) and external limiting membrane (ELM) mean defect length, central foveal thicknesses (CFT), parafoveal macular thickness (MT), ganglion cells and inner plexiform layer (GCL++) thickness, and peripapillary nerve fiber layer (pRNFL) thickness, were compared. <i>Results:</i> Nineteen eyes were included in the IFCG group and 20 eyes in the BBG group. In all cases a FTMH closure was found. CDVA improved at 6 and 12 months in both groups (<i>p</i> < 0.0005); the increase at 12 months was greater in the BBG group (p = 0.036). EZ and ELM defects did not differ between groups at either follow-up time. CFT at 12 months was greater in the BBG group (<i>p</i> = 0.041). A 12-months compared to 6-months MT decrease was present in both groups (<i>p</i> < 0.01). The GCL++ superior inner sector was thicker in the BBG group at 12 months (<i>p</i> = 0.036), as were the superior outer sector (<i>p</i> = 0.039 and <i>p</i> = 0.027 at 6 and 12 months, respectively) and inferior outer sector (<i>p</i> = 0.011 and <i>p</i> = 0.009 at 6 and 12 months, respectively). <i>Conclusion:</i> In our study BBG in I-ILMFS exhibits better long-term CDVA and retinal thickness than does IFCG, suggesting a lesser toxicity from BBG. These findings support the use of BBG over IFCG in I-ILMFS.
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