ImportanceAdditional data are sought regarding treatment options for glaucoma, a major cause of global blindness.BackgroundThe study assessed outcomes following standalone implantation of two second‐generation trabecular micro‐bypass stents and postoperative topical prostaglandin in eyes with open‐angle glaucoma not controlled on two preoperative medications.DesignThe study design is a prospective, nonrandomized, open‐label study at a tertiary‐care ophthalmology centre.ParticipantsSubjects had open‐angle glaucoma with preoperative intraocular pressure of 18–30 mmHg on two medications, a medication washout phase, and post‐washout intraocular pressure of 22–38 mmHg. All subjects (N = 53) have been followed for 18 months.MethodsOne day following implantation of two second‐generation trabecular micro‐bypass stents, subjects started topical travoprost. Medication washout was repeated at month 12.Main Outcome MeasuresThe main outcome measure was the proportion of eyes with intraocular pressure reduction ≥ 20% versus medicated baseline intraocular pressure with reduction of one medication at 12 months.ResultsAt 12 months, 91% of eyes achieved intraocular pressure reduction ≥ 20% with reduction of one medication. All eyes had intraocular pressure ≤ 18 mmHg with reduction of one medication, and 87% had intraocular pressure ≤ 15 mmHg. Mean intraocular pressure on one medication was ≤ 13.0 mmHg (≥ 34% reduction) through 18 months. Mean post‐washout intraocular pressure at month 13 was 33% lower than preoperative unmedicated intraocular pressure. No adverse events occurred through 18 months.Conclusions and RelevanceIn open‐angle glaucoma eyes on two preoperative medications, treatment with two second‐generation trabecular stents and one postoperative prostaglandin resulted in mean intraocular pressure ≤ 13 mmHg with reduction of one medication, with favourable safety. These findings show the utility of second‐generation trabecular bypass with postoperative prostaglandin in patients with open‐angle glaucoma.