To assess the safety and effectiveness of the PRESERFLO® MicroShunt (formerly InnFocus MicroShunt®) in patients with primary open-angle glaucoma (POAG). Design: The MicroShunt, a controlled ab-externo glaucoma filtration surgery device, was investigated in a 2-year, multicenter, single-arm study. Participants: Eligible patients were aged 18–85 years with POAG inadequately controlled on maximal tolerated medical therapy with intraocular pressure (IOP) ≥18 and ≤35 mmHg and/or where glaucoma progression warranted surgery. Intervention: The MicroShunt was implanted as a standalone procedure with adjunctive use of topical Mitomycin C (MMC; 0.2–0.4 mg/mL) for 2–3 minutes. Main Outcome Measures: The primary effectiveness outcome was IOP reduction and success (not requiring reoperation or pressure failures [IOP >21 mmHg and <20% reduction in IOP]) at year 1. Additional endpoints at year 2 included IOP reduction, success, glaucoma medications, adverse events (AEs), and reoperations. Results are reported in the overall population, and subgroups of patients receiving 0.2 or 0.4 mg/mL MMC. Results: In 81 patients, mean (± standard deviation [SD]) IOP reduced from 21.7±3.4 mmHg at baseline to 14.5±4.6 mmHg at year 1 and 14.1±3.2 mmHg at year 2 (P<0.0001). Overall success (with and without supplemental glaucoma medication use) at year 1 was 74.1%. Mean (± SD) number of medications decreased from 2.1±1.3 at baseline to 0.5±0.9 at year 2 (P<0.0001), 73.8% of patients were medication free. Most common non-serious AEs were increased IOP requiring medication and/or selective laser trabeculoplasty (25.9%) and mild to-moderate keratitis (11.1%). There were 6 (7.4%) reoperations and 5 (6.2%) needlings by year 2. In an analysis (post-hoc) according to MMC concentration, overall success was 78.1% (0.2 mg/mL) and 74.4% (0.4 mg/mL; P=0.710). In the 0.2 and 0.4 mg/mL MMC groups, 51.9% and 90.3% of patients were medication-free, respectively (P=0.001). There was a trend towards lower IOP and higher medication reduction 26 in the 0.4 mg/mL MMC subgroup. Conclusions: In this study, mean IOP and glaucoma medication reductions were significant and sustained over 2 years post-surgery. No long-term, sight-threatening AEs were reported. Further studies may confirm potential risk/benefits of higher MMC concentration.