Introduction <p>Most epidemiological studies have found antibiotics to be the most common cause of drug-induced liver injury (DILI). It is unclear what the risk of DILI is associated with different antibiotics.</p> Objective <p>The aim of the study was to assess the frequency of DILI due to the most commonly used antibiotics among inpatients, in a population-based setting.</p> Methods <p>Patients who were treated with the 14 most-used antibiotics at Landspitali University Hospital Iceland 2012–2023, with concomitant: &gt; 5 × upper limit of normal (ULN) of alanine aminotransferase (ALT) and/or &gt; 2 × ULN of alkaline phosphatase (ALP), were identified. If DILI was a potential cause, the Revised Electronic Causality Assessment Method (RECAM) method was used to determine likelihood of DILI.</p> Results <p>Overall 2292 patients fulfilled the inclusion criteria, 52 of whom were found to have DILI, median age 67 (range 21–93) years, 58% females, 17 (33%) with jaundice and three (5.8%) died of liver failure. The most commonly implicated agent was amoxicillin/clavulanate (<i>n</i> = 23) in 1:1327 users (0.075%), ceftriaxone (<i>n</i> = 8) 1:3779 (0.02%), cefazolin (<i>n</i> = 7) 1: 6363 (0.016%), cloxacillin 1:6024 (<i>n</i> = 4) (0.017%), piperacillin/tazobactam (<i>n</i> = 2) 1:1551 (0.097%), vancomycin (<i>n</i> = 2) 1:1966 (0.076%), trimethoprim-sulfamethoxazole (TMP/SMX) (<i>n</i> = 3) 1:1096 (0.091%) and ciprofloxacin (<i>n</i> = 1) 1:10,938 (0.009%). In two cases, more than one antibiotic was considered likely.</p> Conclusions <p>Drug-induced liver injury was found to be a rare adverse effect of antibiotics in a population-based setting. Overall, 33% presented with jaundice but three died of liver failure, all due to amoxicillin/clavulanate, which was the most common cause occurring in around 1 in 1300 users. However, TMP/SMX was associated with the highest proportional risk of DILI.</p>