Autosomal dominant polycystic kidney disease (ADPKD) with renal stones and failed shock-wave lithotripsy (SWL) is a challenging problem. We present a case of ADPKD with large renal stones treated by flexible ureteroscopy and holmium laser lithotripsy, which is usually used to treat renal stones of < 20 mm. This 68-year-old female had suffered from recurrent urinary tract infection and pain on the right side of kidney after several sessions of failed SWL. The imaging study showed a case of ADPKD with two large renal stones (one 30 mm and the other 20 mm in length) in the right-side renal pelvis. We treated the stones using flexible ureteroscopy with holmium laser nephrolithotripsy, which disintegrated the stones into multiple fragments. A second session of ureteroscopy with laser lithotripsy was conducted 30 days later for 2 obstructing residual ureteral stones. She was stone-free at 30 days and 15 months after the last treatment. We recommend flexible ureteroscopy with holmium laser nephrolithotripsy as a valuable alternative for renal stones of > 20 mm in selective cases of ADPKD.