To determine differences in patients' characteristics, operative time and procedures, and perioperative outcomes between prone and supine positioning in percutaneous nephrolithotomy (PCNL) using the Clinical Research Office of the Endourological Society (CROES) PCNL Global Study database. Between November 2007 and December 2009, prospective data were collected on a total of 5803 consecutive patients who were treated over a 1-year period at each of 96 participating global centers. Patients with data on body position were dichotomized into prone or supine PCNL. The majority of PCNL treatments were performed in the prone position (n=4637; 80.3% of sample). Differences in patient characteristics included in the prone group: A greater proportion of males (57.4% vs 52.2%); younger age (48.8 y vs 51.0 y); less frequent history of shockwave lithotripsy (19.5% vs 28.6%); greater frequency of American Society of Anesthesiologists score of 1 (54.7% vs 46.8%); and a Clavien grade of 2 or more (10.0% vs 7.2%). The mean operative time was significantly lower for prone vs supine PCNL (82.7 min vs 90.1 min) regardless of the method of tract dilation, while the stone-free rate was significantly higher (77.0% vs 70.2%). Compared with supine patients, prone patients exhibited higher rates of blood transfusions (6.1% vs 4.3%) and fever (11.1% vs 7.6%), but lower rates of failed procedures (1.5% vs 2.7%). Since operative time and stone-free rates favor prone PCNL, but patient safety favors supine PCNL, the choice of patient position should be tailored to individual patient characteristics and the surgeon's preference.