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Background: Liver toxicity can limit the use of interferon-beta (IFNβ), a well-established treatment for multiple sclerosis (MS). Unfortunately, known risk-factors for IFNβ-associated liver toxicity are few and of limited clinical utility. Susceptibility to drug-induced toxicity is influenced by genetic factors affecting hepatic lipid metabolism and drug-metabolizing activity., Methods: We designed a retrospective, multicentre study to evaluate whether specific polymorphisms in genes involved in hepatic lipid metabolism are associated with a higher risk of developing IFNβ-induced hepatotoxicity. The following single nucleotide polymorphisms were examined: rs738409 C > G in PNPLA3; rs4880 C > T in SOD2; rs3750861 C > T in KLF6; rs13412852 C > T in LPIN1; rs58542926 C > T in TM6SF2. Liver toxicity was defined as a new increase of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) plasma levels above the laboratory upper normal limit after the start of IFNβ treatment., Results: One-hundred-thirteen MS patients were enrolled and twenty-nine experienced liver toxicity. Logistic regression analysis revealed that the PNPLA3 variant was significantly associated with the occurrence of liver toxicity. No associations were found between other polymorphisms and liver toxicity., Conclusions: The results of our exploratory study suggest that the PNPLA3 variant can help to identify those patients at higher risk of IFNβ toxicity. The stratification of the risk of liver toxicity could increase the safety of IFNβ therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)