Purpose To report the effectiveness and safety of 5-fluorouracil (5-FU)-augmented Xen45 implantation in primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PEXG). Methods This single-center, retrospective chart review study included 29 eyes that underwent 5-FU-augmented Xen45 implantation. Main outcome measures were intraocular pressure (IOP) levels and number of glaucoma medications. Surgical success was defined as IOP <= 21 mmHg and >= 20% reduction from preoperative levels without (complete success) or with (qualified success) glaucoma medications and without further glaucoma surgery at last follow-up. All postoperative interventions and complications were also noted. Results The mean age of the patients was 67.5 +/- 10.3 years, and the mean follow-up time was 23.2 +/- 12.6 months. Mean IOP was 24.5 +/- 8.7 mmHg and decreased by 30.2% at 12 months, 24.9% at 24 months, and 31.7% at final visit (p < 0.001, p = 0.006, p > 0.001, respectively). Mean number of glaucoma medications decreased from 2.83 preoperatively to 0.71 at 12 months, 0.87 at 24 months, and 0.86 at final visit (p < 0.001). At final visit, the complete success rate was 48.3%, qualified success rate was 69%, and 62.1% of the eyes were free of glaucoma medications. Needling was performed in 7 eyes (24%). Adverse events included choroidal detachment in 5 eyes, hyphema in 2 eyes, and endophthalmitis in 1 eye. Conclusion 5-FU-augmented Xen45 implantation in POAG and PEXG patients provided safe and effective IOP lowering with significant reduction of glaucoma medications up to 3 years.