This review examines the evidence for antibiotic prophylaxis in endoscopic retrograde cholangiopan-creatography (ERCP), and provides detailed advice about suitable antibiotic regimens in appropriate high-risk patients. Ascending cholangitis and infective endocarditis are potential complications of endoscopic ERCP. The pathophysiology of these two complications is quite separate and different sub-groups of patients require prophylaxis with appropriate antibiotic regimens. Ascending cholangitis results from bacterial infection of an obstructed biliary system, usually from enteric Gram-negative microorganisms, resulting in bacteraemia. There is incomplete drainage of the biliary system after ERCP in up to 10% of patients who require stenting. Antibiotics started in these patients will probably reduce the frequency of cholangitis by 80%. If antibiotics are restricted to this group, approximately 90% of all patients having an ERCP will avoid antibiotics, but 80% of cholangitic episodes will be prevented. Infective endocarditis may result from the bacteraemia caused at the time of the ERCP in patients with an abnormal heart valve. Antibiotic prophylaxis, in particular covering alpha-haemolytic streptococci, should be started before the procedure in this defined high-risk group.