The objective of this study was to evaluate the safety and efficacy of flexible ureteroscopy (FURS) and holmium:YAG laser lithotripsy for the treatment of upper urinary tract stones in patients on active oral anticoagulants. The records of 1081 patients who underwent flexible ureteroscopic holmium:YAG (Ho:YAG) laser lithotripsy for upper ureteral and renal calculi from 1999 to 2015 were retrospectively reviewed. A total of 84 patients on continuous oral anticoagulation or antiplatelet therapy (warfarin, aspirin, or clopidogrel) were identified. Of these patients, 40 were on warfarin, 25 on aspirin, 11 on clopidogrel, and 8 on both aspirin and clopidogrel. The drugs were not discontinued. The baseline characteristics, indications for anticoagulation therapy, perioperative data, stone-free rate, and complications were documented. Evaluation of outcomes was assessed at 1-, 3-, and 6-month follow-up postoperatively. Mean stone size was 19.7 ± 9.4 (range 8 to 31 mm). Twenty patients had upper ureteral and 64 patients had intrarenal calculi. Two patients had bilateral renal calculi. Mean operation time was 78.2 ± 23.8 min (range 17 to 144 min). Two procedures (2.3%) in warfarin group were terminated due to persistent bleeding causing visual impairment. No transfusions were required. The mean serum hemoglobin levels did not change significantly (12.9 ± 3.7 to 12.2 ± 3.3 g/dL). No thromboembolic or cardiac adverse events were observed perioperatively. The double-j (DJ) ureteral catheterization time was 29.6 ± 9.3 days (range 14 to 68 days) and the hospital stay was 1.6 ± 0.6 days (range 1 to 4). The stone-free rate was 95.2% (80 patients) at 6 months. Flexible ureteroscopic Ho:YAG laser lithotripsy in patients requiring long-term anticoagulation therapy seems to be a safe and effective procedure and should be considered as a first-line treatment option in such patients for the surgical management of upper urinary tract stones.