Drug-induced liver injury (DILI) remains one of the most challenging diseases due to the absence of diagnostic tests and biomarkers. DILI usually presents as an acute hepatitis-like picture requiring extensive differential diagnosis, hepatitis E virus (HEV), which is considered a rare condition in Spain, is not usually ruled out during acute hepatitis assessment. Analysis of a cohort of 180 patients from the Spanish DILI Registry diagnosed with DILI was undertaken. We analyzed HEV immunoglobulin (Ig) G and M from two groups of serum samples based on the time point of collection (27 samples during the episode of liver damage and 153 at different time points after resolution). In patients showing anti-HEV-IgM+, AgHEV and RNA-HEV were performed. Out of 180 patients included, 60 (33, 3%) were tested positive for anti-HEV IgG and 6 for anti-HEV IgM (1 positive for HEV-RNA and 2 for Ag-HEV). In the group of samples collected during the episode, 3/27 (11%) were positive for IgM-HEV. Table. Demographic and clinical data of patients with positive IgM anti-HEV.Tabled 1Case nºAge (years)SexSuspected DrugLatency (days)Peak ALT(1) or AST(2)HEV RNAAg HEV149FemaleParacetamol91840 (2)NegativePositive274MaleCefditoren404191 (1)PositivePositive326FemaleDexketoprofen81561 (1)NegativeNegative456FemaleIsoniazid27 954 (1)NegativeNegative535MaleErythromycin272469 (1)NegativeNegative675MaleAmoxicillin42967 (1)NegativeNegative Open table in a new tab Evidence of hepatitis E infection is present in a significant number of patients suspected to have DILI. Seroprevalence of IgG HEV is also very high. Hepatitis E should be ruled out in all patients suspected to suffer from DILI in Spain.