Background and Aim: Quinolones are globally popular antibiotics with proven potency, broad coverage, and reasonable safety. However, some concerns were raised as to their possible association with acute liver failure (ALF). The aim of this study is to assess ALF risk within 30 days of receiving a systemically administered quinolone antibiotic, in individuals with no history of liver/diseases. Methods: We conducted a nested case-control study using electronic health records from the Cerner Health Facts. The initial cohort (n = 35 349 943) included all patients who were admitted between 2000 and 2016, with no history of liver diseases, and had a minimum medical history of one year. Eligible cases were inpatients who were first diagnosed with ALF between 2010 and 2015. Using incidence density sampling, each case was matched with up to five unique controls by sex, race, age at index encounter, and period-at-risk. We used conditional logistic regression to calculate the odds ratio and 95% confidence interval for ALF risk, upon adjusting for exposure to other medications, and major confounders (diabetes mellitus and alcohol abuse). We used the STROBE Statement for reporting on our study. Results: We identified 3151 cases and 15 657 controls. Our primary analysis did not reveal an association between quinolones and ALF risk. However, some risk was identified among those with no or few comorbidities, those ≤ 60 years of age, women, men, African Americans, and Caucasians. Conclusion: Although our study does not suggest an overall association between quinolones and ALF, elevated risks seen in some subgroups warrant further investigation. quinolones, may play a role in the development of drug-induced liver injury. 4,13,14 Acute liver failure is a serious disease involving rapid, progressive, and likely severe loss of hepatic cells, which may involve transient elevations of liver enzymes up to severe liver damage requiring transplantation. [5][6][7] Such deterioration takes place within 4 weeks [15][16][17][18][19] following exposure to different factors such as medications, nutritional, and herbal supplements, bacteria, viruses, and toxins. 5,6,8,10 Annual ALF incidence in the United States reportedly ranges between one and six per million, while comprising 7% and 6% of liver-related transplants and deaths, respectively. 15 Possible mechanisms for hepatotoxicity include production of reactive metabolites, 3,4,7 or triggering an immunologic response to the administered quinolone. 3,20 However, a definitive pathophysiology remains to be confirmed. 4,7 Whereas quinolone-associated ALF risk has been investigated in some epidemiological studies, 4,7,21,22 and spontaneous adverse