Enterobacteriaceae peritonitis is a serious complication in peritoneal dialysis (PD), but the clinical course of PD-related Enterobacteriaceae peritonitis remains unclear. We reviewed all Enterobacteriaceae peritonitis in our dialysis unit from 1995 to 2004. During this period, there were 1748 episodes of peritonitis recorded; 210 episodes (12.0%) in 123 patients were caused by Enterobacteriaceae. The most common species was Escherichia coli, accounting for 111 episodes. The primary response rate was 84.8% and complete cure rate was 58.1%. The presence of exit site infection was associated with a lower complete cure rate (43.2 versus 61.3%, P = 0.034). A total of 82 episodes (39.0%) did not respond to single antibiotic treatment despite sensitivity in vitro, and a second antibiotic was added. Patients treated with two antibiotics had a marginally lower risk of relapse and recurrence than those with one antibiotic (21.4 versus 36.1%, P = 0.051). The episodes that had recent antibiotic therapy had a marginally lower complete cure rate (49.3 versus 62.8%, P = 0.06). There was a gradual increase in the prevalence of resistance to several commonly used antibiotics over the years. Recent antibiotic therapy was associated with resistance to cefotaxime, ceftazidime, cefoperazone/sulbactam, and piperacillin/tazobactam. We conclude that Enterobacteriaceae peritonitis is a serious complication of PD. Recent antibiotic therapy is the major risk factor of antibiotic resistance. Exit site infection, and probably recent antibiotic therapy, is associated with poor therapeutic response. Contrary to the current recommendation, treatment with two antibiotics may reduce the risk of relapse and recurrence.