Consumption of food containing antibiotic residues can cause direct toxic effects, such as allergic reactions, or indirect effects, like the possibility to contribute to the development of antimicrobial resistance. It is essential for consumer food safety, as well as for public health, to monitor antibiotics in foods of animal origin intended for human consumption, particularly in piglets, a highly consumed meat in Portugal. Concerning the lack of regulations regarding the validation criteria for the ToF-MS (time-of-flight mass spectrometry) drug residues determination, this study presents an approach for the use of UHPLC (ultra-high-pressure-liquid-chromatography)-ToF-MS not only for screening but also for confirmatory purposes of 45 antibiotics from 7 different classes. Thus, a method was optimized and validated in accordance with Decision 2002/657/EC by evaluating CCα, CCβ, specificity, selectivity, recovery, ruggedness, repeatability and reproducibility. For antibiotics with no MRL set, the lowest values achieved for CCα and CCβ were, respectively, of 0.1 μg kg and 0.2 μg kg for cinoxacin. Regarding precision, the CV values obtained ranged from 5% to 21% for repeatability and from 6% to 22% for reproducibility. Recoveries were calculated falling between 82% and 120%. After validation, the method was used to analyse piglet liver samples. Antibiotic residues were determined in 47% of the 21 analysed samples. Nevertheless, all the antibiotics were detected at concentrations below the MRLs.Copyright © 2020 Elsevier B.V. All rights reserved.