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A severe prolonged illness that was characterized by deep jaundice and debilitating pruritus occurred in five patients after the use of flucloxacillin. The symptoms and signs of liver disease took at least two months to resolve; after four‐ to nine‐months' follow‐up, liver enzyme activities have remained abnormal in all patients. Examination of liver biopsy specimens showed severe cholestasis in all cases, with evidence of significant bile‐duct injury in three cases. In one patient, in whom symptoms have persisted for nine months, examination of a liver biopsy specimen showed marked bile‐duct depletion. All patients were seen during a four‐month period and it is felt that flucloxacillin‐induced liver disease probably has been underdiagnosed and underreported. The use of flucloxacillin has been increasing rapidly and it is anticipated that more cases of flucloxacillin hepatotoxicity will occur in the future.