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The purpose of this study was to investigate the safety profile of the 23-gauge sutureless vitrectomy system in the treatment of epiretinal membranes compared with standard 20-gauge vitrectomy.A retrospective case comparison of 20-gauge and 23-gauge vitrectomy performed in 167 and 64 eyes, respectively, by the same surgeon. Intraoperative and postoperative complications, duration of surgery, and postoperative visual acuity results were evaluated.Postoperative hypotony occurred significantly more often in the 23-gauge group [9.4% (n = 6) vs. 0% (n = 0), P < 0.001]. With the 23-gauge system, the incidence of retinal detachment was 1.6% (n = 1), vitreous hemorrhage was 0%, and endophthalmitis was 1.6% (n = 1). Patients with 20-gauge vitrectomy developed retinal detachments in 1.8% (n = 3), vitreous hemorrhages in 1.2% (n = 2), and endophthalmitis in 2.4% (n = 4). The mean overall duration of surgery was significantly shorter in the 23-gauge procedures with 23.1 ± 6.5 minutes compared with 34.5 ± 9.1 minutes in the 20-gauge procedures (P < 0.05). At postoperative Day 2, patients with 23-gauge vitrectomy regained preoperative mean best-corrected visual acuity of 20/60. Patients who had 20-gauge vitrectomy experienced a statistically significant decrease of visual acuity from 20/80 to 20/100 (P < 0.05).Twenty-three-gauge vitrectomy in epiretinal membrane surgery is comparable with 20-gauge vitrectomy and is a safe method with a low complication rate. However, the incidence of postoperative hypotony is more frequent using the 23-gauge system.