The use of flexible ureteroscopy (URS) for nephrolithiasis has been rapidly expanding. Initially, safety guidewires were maintained alongside the ureteroscope during stone manipulation to prevent loss of access and allow stent insertion in the event of perforation. We intend to determine the safety of flexible URS without a separate safety guidewire in a large series of patients. A retrospective chart review was performed on all cases of flexible URS with laser lithotripsy performed by a single surgeon from August 2003 to May 2008. Preoperative patient characteristics, radiographic stone sizes, operative findings, and postoperative outcomes were recorded. Patients with renal or ureteropelvic junction (UPJ) stones were isolated for a qualitative data analysis. Flexible URS was performed on 305 kidneys in 246 consecutive patients, of which 59 cases were bilateral. Cases were subdivided into complicated and uncomplicated. Two hundred seventy cases were uncomplicated and performed without a safety guidewire. No intraoperative complications resulted from the lack of a safety guidewire, including no cases of lost access, ureteral perforation/avulsion, or need for percutaneous nephrostomy tube. Thirty-five cases were complicated, necessitating a safety guidewire. Of these, 16 had concomitant obstructing ureteral stones, 5 had encrusted ureteral stents, and 14 had difficult access because of large stone burden or aberrant anatomy. This study demonstrates that, in a large series of patients, a safety guidewire was not necessary for routine cases of flexible URS with laser lithotripsy on renal or UPJ stones. Particular cases with complicated anatomy, difficult access, concomitant ureteral stones, simultaneous stone basketing, or bulky stone burden still necessitate use of a safety guidewire because of increased risk of adverse outcomes.