The efficacy of prophylactic parenteral antibacterials, with or without selective decontamination of the digestive tract, was compared in patients with acute liver failure (ALF) or severe acetaminophen hepatotoxicity. One hundred eight patients were randomized on admission to receive intravenous ceftazidime and flucloxacillin, plus either oral and enteral decontamination with colistin, tobramycin, and amphotericin B (group 1), or enteral amphotericin B alone (group 2). The two groups were comparable with respect to age, gender, etiology, coma grade on admission, international normalization ratio, presence of renal failure, Acute Physiology and Chronic Health Evaluation II score, and indicators of poor prognosis. Patients were monitored for clinical and microbiological evidence of infection. There were 15 episodes of infection in 10 of 47 patients (21%) in group 1 and 17 episodes in 12 of 61 patients (20%) in group 2. No differences in incidence, site, and causative organisms of infection were observed between the two groups. Overall, the incidence of infection was significantly higher in patients who developed encephalopathy than in those who did not. In patients who on arrival were not encephalopathic, the development of infection was associated with progression to coma. Duration of Liver Intensive Care Unit (LICU) stay was an independent risk factor for the development of infection. Parenteral antibiotics are effective at reducing the risk of infection in patients with ALF; enteral decontamination provided no additional benefit.