We performed a prospective study to examine the epidemiology and microbiology of peritonitis complicating acute intermittent peritoneal dialysis (IPD) performed in an in-hospital setting for the management of acute and chronic renal failure and to see the effect of a closed-drainage system on altering the frequency and cause of peritonitis. Over a 15-month period, 79 patients were treated with acute IPD for a total of 136 treatments each ranging in length from 2 to 40 days (median, 4 days). The majority of cases had acute renal failure (ARF; 65%) and were treated in intensive care units (ICUs; 74%) with serious comorbid conditions (60%). About half were treated with a two-bag, ventable (open)-drainage system with unprotected spikes, and the other half were treated with a single-bag, spike-protected, closed-drainage system. There were 27 cases of peritonitis for a rate of 4.5 cases/100 patient-days at risk. About half were gram-positive infections; the remainder were gram-negative or mixed (25%) or Candida sp (25%). The use of a closed-drainage system reduced the incidence of system-related peritonitis from 3.6 to 1.5 cases/100 patient-days. There was a high rate of peritonitis in the first 48 hours of treatment, which fell to a low stable rate thereafter and remained so for up to 15 days of continuous IPD. The use of a closed-drainage system eliminated the early (< 48 hours) high rate of peritonitis and maintained a low constant rate of peritonitis throughout treatment. There was an association of ARF and severe comorbid disease with more virulent organisms (gram-negative, mixed, and Candida sp), which, in turn, were both associated with antecedent broad-spectrum antibiotic therapy. Random positive surveillance cultures showed a frequency distribution similar to that of peritonitis cases over the duration of treatment, but with less virulent organisms. Peritonitis in acute IPD occurs when large or repeated inocula of organisms from the prevailing flora overwhelm the peritoneal immune clearance mechanisms. Prolonged courses of broad-spectrum antibiotic therapy provide no protection, but shift the resulting infecting flora toward more virulent pathogens. A closed-drainage system provides one method to reduce the frequency of peritoneal contamination.