OBJECTIVE To evaluate the safety and efficacy of ultrasonography (US)-guided renal access in percutaneous nephrolithotomy (PCNL), as compared with conventional fluoroscopy-guided renal access in a prospective randomized trial. PATIENTS AND METHODS From January 2008 to October 2009, 224 patients with renal calculi undergoing PCNL were randomized into two groups. Group 1 (112 patients) underwent PCNL using only fluoroscopy-guided renal access; while in group 2 (112 patients), US guidance for puncture was used in addition to fluoroscopy. The inclusion criteria were: normal renal functions, American Society of Anesthesiology scores 1 or 2, absence of congenital abnormalities, aged 15-70 years, and anticipated single-tract procedure. The patients in both groups were matched for age, sex, and stone characteristics. The Student t-test was used for statistical analysis with an allowable error of 5%. RESULTS The mean time to successful puncture was 3.2 min and 1.8 min in group 1 and group 2, respectively (P < 0.01). The mean duration of radiation exposure to successful puncture was 28.6 s in group 1 and 14.4 s in group 2 (P < 0.01). The mean numbers of attempts for successful puncture in the desired calyx was 3.3 in group 1 as compared with 1.5 in group 2 (P < 0.01). The meantime taken for tract formation in group 1 was 7.4 min with radiation exposure of 82 s, while in group 2 it took 4.8 min with radiation exposure of 58 s (P < 0.01). Successful access was achieved in all patients. All patients were stone-free at the end of the operation. The hospital stay (2-3 days) was same in both groups. There was no incidence of significant bleeding requiring transfusion during or after surgery. All the patients were followed-up for a >= 6 months. CONCLUSION US-guided puncture in PCNL helps in increasing accuracy of puncture and decreasing radiation exposure for the surgical team and the patients.