This prospective, non-randomized, open-label, multicenter, 2-year study evaluated the effectiveness and safety of an ab interno gelatin implant as a primary surgical intervention for medically uncontrolled primary open-angle glaucoma (POAG). The study included 218 eyes with baseline intraocular pressure (IOP) between 18 and 33 mmHg on 1-4 topical medications. The gelatin implant was implanted either alone or in combination with cataract surgery. The primary outcomes were changes in mean IOP and medication count at 12 and 24 months. The modified intent-to-treat population included 202 eyes. Mean IOP decreased by 6.5 mmHg (SD 5.3) and medication count decreased by 1.7 (SD 1.3) mmHg at 12 months, and by 6.2 mmHg (SD 4.9) and 1.5 (SD 1.4) mmHg at 24 months, respectively (all P < 0.001). The clinical success rate was 67.6% at 12 months and 65.8% at 24 months. Overall, 51.1% (12 months) and 44.7% (24 months) of eyes were medication-free. The implant safety profile was favorable compared to trabeculectomy and tube shunts. The gelatin implant effectively reduced IOP and medication needs over 2 years in POAG uncontrolled medically, with an acceptable safety profile.This prospective, non-randomized, open-label, multicenter, 2-year study evaluated the effectiveness and safety of an ab interno gelatin implant as a primary surgical intervention for medically uncontrolled primary open-angle glaucoma (POAG). The study included 218 eyes with baseline intraocular pressure (IOP) between 18 and 33 mmHg on 1-4 topical medications. The gelatin implant was implanted either alone or in combination with cataract surgery. The primary outcomes were changes in mean IOP and medication count at 12 and 24 months. The modified intent-to-treat population included 202 eyes. Mean IOP decreased by 6.5 mmHg (SD 5.3) and medication count decreased by 1.7 (SD 1.3) mmHg at 12 months, and by 6.2 mmHg (SD 4.9) and 1.5 (SD 1.4) mmHg at 24 months, respectively (all P < 0.001). The clinical success rate was 67.6% at 12 months and 65.8% at 24 months. Overall, 51.1% (12 months) and 44.7% (24 months) of eyes were medication-free. The implant safety profile was favorable compared to trabeculectomy and tube shunts. The gelatin implant effectively reduced IOP and medication needs over 2 years in POAG uncontrolled medically, with an acceptable safety profile.