To evaluate 5-year safety and efficacy of 2 trabecular micro-bypass stents versus prostaglandin as initial stand-alone treatment for newly diagnosed, treatment-naive primary open-angle glaucoma (POAG). Prospective, randomized, controlled, multi-surgeon clinical trial. Enrolled eyes (n= 101) were phakic and had a confirmed POAG diagnosis, normal angle anatomy, mean diurnal intraocular pressure (IOP) 21 to 40 mmHg, and vertical cup-to-disc (C:D) ratio ≤0.9. Eyes were randomized (1:1) to receive either 2 stents (iStent trabecular micro-bypass; Glaukos Corporation, San Clemente, CA) or once-daily topical travoprost. The primary and secondary efficacy end points were the change from screening in mean diurnal IOP at months 12 and 24, respectively, without glaucoma surgery or add-on medication (any medication in stent eyes or a second medication in travoprost eyes). Two additional secondary end points were the proportion of eyes achieving treatment success at months 12 and 24, defined as IOP 6 to 18 mmHg without additional medication or glaucoma surgery. This report shows these efficacy measures through 60 months. Safety measures included best-corrected visual acuity, C:D ratio, visual field, pachymetry, complications, and adverse events. Of 101 enrolled eyes (54 stent eyes, 47 travoprost eyes), 90 eyes (49 stent eyes, 41 travoprost eyes) completed 5-year follow-up. Five-year mean diurnal IOP was 16.5±1.2 mmHg in stent eyes (35.3% reduced vs. 25.5±2.5 mmHg preoperatively; P < 0.0001) and 16.3±1.9 mmHg in travoprost eyes (35.1% reduced vs. 25.1±4.6 mmHg preoperatively; P < 0.0001). During follow-up, add-on medication was initiated in 12 stent eyes (22.2% of the initial 54-eyes) and 18 travoprost eyes (38.3% of the initial 47-eyes). By 5 years, 17% (6/35) of stent eyes and 44% (14/32) of travoprost eyes needed add-on medication to control IOP (P= 0.017). Treatment success was achieved in 77% (27/35) of stent eyes and 53% (17/32) of travoprost eyes (P= 0.04). Both groups exhibited excellent safety. This prospective randomized trial demonstrates 5-year effectiveness and safety of 2 trabecular bypass stents in patients with newly diagnosed, treatment-naive POAG, with comparably favorable outcomes as topical prostaglandin.