Precis: This study confirms the safety and efficacy of XEN gel stents in the management of pseudoexfoliative glaucoma 2 years after implantation, with success rates similar to primary open-angle glaucoma regardless of the definition of success. Purpose: To compare the long-term safety and efficacy of XEN gel implant surgery (Allergan Inc., Irvine, CA) in patients with pseudoexfoliative glaucoma (PEXG) and primary open-angle glaucoma (POAG). Setting: Prospective, interventional study in a tertiary glaucoma center. Methods: A total of 110 eyes of 85 patients with POAG (57 eyes) or PEXG (53 eyes) and uncontrolled intraocular pressure (IOP) despite medical treatment underwent combined XEN+cataract surgery or standalone XEN surgery. Mean IOP, mean number of medications, needling rates, and incidence of adverse effects were compared between the 2 groups. Complete surgical success was defined as an unmedicated IOP <= 12, 15, 16, or 18 mm Hg at 2 years, both with and without a 20% reduction from baseline. Results: Combined XEN+cataract surgery was performed in 72% of POAG and 76% of PEXG eyes (P=0.67), the remainder underwent standalone XEN surgery. Patient characteristics were similar between the 2 groups except for older age for the patients with PEXG (78.5 +/- 8.5 vs. 71.3 +/- 8.7 y; P<0.005). Mean medicated IOP were 19.8 +/- 5.8 mm Hg (POAG) versus 19.8 +/- 8.2 mm Hg (PEXG) at baseline (P=0.98), and 14.5 +/- 3.6 mm Hg (-26.8%) versus 14.2 +/- 3.8 mm Hg (-28.3%), respectively, at 2 years (P=0.75). Mean medications concomitantly dropped from 1.9 +/- 1.6 (POAG) versus 2.0 +/- 1.3 (PEXG) to 0.6 +/- 0.9 versus 0.4 +/- 0.7, respectively (P=0.29). Using the 16 mm Hg threshold, 51.4% (POAG) versus 57.1% (PEXG) eyes achieved complete success (P=0.70) at 2 years. The difference in success rates between the 2 groups was not statistically significant under any of the definitions of success. By 24 months, needling was performed in 42.8% (POAG) and 43.2% (PEXG) (P=0.64), with an average time to needling of 162.8 and 134.9 days, respectively (P=0.46). The rates of adverse effects were 30.6% (POAG) and 36.4% (PEXG) (P=0.66), and additional glaucoma surgeries were carried out in 14.3% (POAG) versus 15.9% (PEXG) (P=0.89). Conclusions: The XEN gel implant as a standalone or combined procedure demonstrated similar efficacy and safety results in PEXG and POAG eyes.