Peritonitis is the most common cause of dialysis failure in children on chronic peritoneal dialysis. We performed a prospective study of 501 peritonitis episodes in 44 pediatric dialysis centers located in 14 countries that examined peritonitis etiology, efficiency of opinion-based management guidelines, and final outcomes. Culture-negative incidence varied significantly from 11% in North America to 67% in Mexico. Argentina and North America had the highest rate of Gram-negative episodes. Pseudomonas-based peritonitis was eightfold more common in the United States than in Europe, and correlated with the frequency of exit site cleansing and topical mupirocin administration. Significant regional variation in antibiotic susceptibility was noted for the first generation cephalosporins and aminoglycosides. Initial response rates to standardized empiric antibiotic treatment did not differ between regions; however, final outcomes were significantly less favorable in Eastern Europe. The wide regional variation in culture-negative peritonitis, and the distribution and antibiotic susceptibilities of causative bacteria needs to be taken into consideration when the guidelines for empiric therapy of pediatric dialysis-associated peritonitis are revised.