Aim: To compare a standard 25-gauge vitrectomy system with a new ultrahigh-speed (UHS) 25-gauge system with duty cycle control for pars plana vitrectomy. Methods: In this prospective, controlled clinical trial, 120 patients (divided into 2 groups of 60 patients) underwent a 3-port pars plana vitrectomy for the treatment of epiretinal membranes, macular holes, retinal detachment, and complications of diabetic retinopathy. Evaluations were performed preoperatively, intraoperatively, on the first 3 postoperative days, and at 1 week, 1 month, and 3 months. Main outcome measures were vitrectomy time, induction of posterior vitreous detachment, and intra-and postoperative complications. Vitrectomy time included retinal manipulation, but did not include wound opening and closure. Results: The duration of surgery was significantly different between the groups. Patients in the new UHS 25-gauge group had a significantly shorter duration of vitrectomy time (P < 0.0001). Mean overall vitrectomy time was 1,583.7 +/- 875.4 seconds (26 minutes) in the standard 25-gauge group and 1,106.3 +/- 575.9 seconds (18 minutes) in the UHS 25-gauge group. Twenty-nine patients (48.3%) in the standard group and 27 patients (45.0%) in the UHS group experienced induction of posterior vitreous detachment. Thirteen patients (21.7%) in the standard 25-gauge group and 1 patient (1.7%) in the new UHS group had intraoperative iatrogenic retinal breaks. Conclusion: The new-generation UHS 25-gauge system may provide a new paradigm of high-flow, smaller-diameter instrumentation, thus increasing the efficiency of the small-gauge technique and the safety of the surgery. RETINA 31:2007-2013, 2011