Purpose To evaluate the role of combination of N-acetylcysteine with stepwise ramping voltage in renal protection against the ischemic, vascular and oxidative effects of extracorporeal shock wave lithotripsy. Patients and methods A prospective randomized trial on 164 adult patients scheduled for ESWL for single renal stones. Patients with radio-lucent stones, diabetes, hypertension, febrile UTI, and preoperative albuminuria were excluded from the study. Patients were randomized into one of four groups. Group A patients received maximal fixed voltage of ESWL. Group B patients received stepwise ramping voltage of ESWL. Group C patients received fixed maximal voltage with N-acetylcysteine (NAC) 600 mg/bid from 48 h before to 24 h after the procedure. Group D patients received gradual ramping voltage with NAC. Urinary β2-microglobulin, 24 h albumin and N-acetyl-β-d-glucosaminidase/creatinine ratio at 1 day and 5 days post- ESWL and the stone free rate at 2 weeks were measured. Results Group D was the only group that showed no significant difference pre and post ESWL in urinary albumin, β2- microglobulin and N-acetyl-β-d-glucosaminidase/creatinine ratio. Post hoc analysis revealed no significant difference between group B and group C in albumin, β2-microglobulin N-acetyl-β-d-glucosaminidase/creatinine ratio, but both of them had significantly lower levels than group A and significantly higher levels than group D. There was no statistically significant difference between all groups in the stone free rate at 2 weeks. Conclusion N-acetylcysteine protects the kidney against ESWL-induced renal injuries especially if combined with stepwise ramping voltage.