AIMS:To provide additional quantification of theriskofflucloxacillin-relatedliverdiseaseand to describe time trends influcloxacillinprescribingin theUK.METHODS:This was acohortstudyusingdatafrom theUKGeneralPracticeResearchDatabase. We identified patients with a first-time prescription forflucloxacillinor, for comparison, oxytetracycline from 1992 to 2002 and cases who developed clinically documentedcholestaticliverdiseaseof uncertain origin after first-time use of these drugs. We also determined the annual frequency of first-time use offlucloxacillinfrom 1991 to 2000.RESULTS:We identified 283 097 and 131 189 first-time users offlucloxacillinand oxytetracycline, respectively. Theriskofcholestaticliverdiseaseper 100 000 first-time users was 8.5 (95% CI 5.4, 12.6) in the 1-45 days and 1.8 (95% CI 0.6, 4.1) in the 46-90 days after startingflucloxacillin, and 0.8 (95% CI 0.02, 4.3) in the 1-45 days after starting oxytetracycline. The frequency of first-time use offlucloxacillinremained stable between 1991 and 2000.CONCLUSIONS:Flucloxacillinis now established as an important cause ofcholestaticliverdisease. Warnings about theriskhave not had an impact onprescribingpractices in theUK, where it remains the predominantly prescribed antistaphylococcal oral antibiotic. This situation in theUKis in sharp contrast to regulatory actions and changes inprescribinghabitsin Australia after identification of theriskof cholestasisassociatedwithflucloxacillin, and to the predominant use of the alternative drug dicloxacillin in the USA.