PURPOSE: Selective laser trabeculoplasty (SLT) is a first-line treatment for glaucoma and ocular hypertension. However, due to insufficient comparative evidence in efficacy and safety, several SLT treatment protocols are currently used in practice. The objective of this trial was to compare the clinical outcomes of the 4 most significant SLT variants. DESIGN: Prospective, multicenter, masked, randomized controlled trial (RCT). PARTICIPANTS: Four hundred patients with glaucoma or ocular hypertension. The cohort consisted of both treatment-naive patients and patients undergoing glaucoma treatment, at different stages of disease. METHODS: Selective laser trabeculoplasty was performed with 50 ± 5 laser spots in 180 degrees or with 100 ± 10 spots in 360 degrees. The laser power was titrated to either just below the cavitation bubble level ("standard energy") or to a level producing cavitation bubbles at 50% to 75% of laser applications ("high energy"). Thus, 4 different treatment protocols were included - 180/standard, 180/high, 360/standard, and 360/high. The study adhered as close as possible to regular clinical management, but within a scientific framework. MAIN OUTCOME MEASURES: Reduction of intraocular pressure (IOP) 1 to 6 months after SLT. The proportion of patients achieving a 20% IOP reduction without any further intervention. Time to glaucoma treatment escalation in a Kaplan-Meier survival analysis. RESULTS: SLT performed with the 360/high protocol was shown to be superior regarding all primary endpoints. The IOP reduction 1 to 6 months after SLT was 5.4 mmHg in the 360/high group, compared to 3.4, 3.2, and 4.2 mmHg with the 180/standard, 180/high, and 360/standard protocols, respectively (P < 0.001). Furthermore, the success rate after 6 months was significantly higher -58.3%, compared with 30.2%, 29.3%, and 41.7% (P < 0.001). The median time to glaucoma treatment escalation was more than twice as long with 360/high SLT -1323 days, compared to 437 days, 549 days, and 620 days (P < 0.001). Although postoperative discomfort was more frequent with the 360/high protocol, symptoms were generally mild and transient. Adverse events were rare in all groups. CONCLUSIONS: The magnitude and longevity of SLT results increases substantially if SLT is performed according to the 360/high protocol, without compromising safety. Therefore, we recommend that 360/high SLT be considered as standard treatment. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.