Purpose: Pulse-modulated holmium:YAG (Ho:YAG) and SuperPulse thulium fiber laser are high-power laser systems used for retrograde intrarenal surgery. We conducted a prospective randomized trial to compare lithotripsy efficiency, complications, and stone-free rates. Materials and Methods: Patients with CT-confirmed intrarenal stones between 5 and 20 mm were randomly assigned to pulse-modulated Ho:YAG (Moses 2.0, 120 W) or SuperPulse thulium fiber laser (60 W). The primary outcome was absolute (0 fragment) stone-free rate 6 weeks postoperatively evaluated by CT. Secondary outcomes included residual fragment size, laser efficiency, and postoperative complications. Categorical variables were compared using X-2 or Fisher exact tests. Continuous variables were analyzed with Mann-Whitney U tests. Results: Sixty-six patients were randomized to pulse-modulated Ho:YAG (n = 33) or SuperPulse thulium fiber laser (n = 33). Absolute stone-free rates were 79% and 82%, respectively (P = .8). Less than 3 mm residual fragments were observed in 18% and 6.1% (P = .3) and >= 3 mm residual fragments in 3% and 12% (P = .4), respectively. Total energy used (3.4 vs 3.1 kJ, P = .8) and lasing time (9.4 vs 12.8 minutes, P = .3) were similar. Laser ablation efficiency (0.038 vs 0.055 mm(3)/J, P = .16), laser activity (46% vs 56%, P = .07), and laser ablation speed (0.40 vs 0.42 mm(3)/s, P > .9) did not differ. Emergency department visits (3.0% vs 6.1%, P > .9) and complications (6.1% vs 9.1%, P > .9) were similar. Conclusions: We found no discernible differences between the high-power pulse- modulated Ho:YAG and SuperPulse thulium fiber laser for treatment of renal stones between 5 and 20 mm in terms of stone-free rates by CT scan, laser efficiency, and complications in our single-center study.