Abstract: Background & Aims Hepatitis E virus (HEV) genotype (gt) 3 infections are prevalent in high income countries and display a wide spectrum of clinical presentations. Host – but not viral – factors are reported to be associated with worse clinical outcomes. Methods Demographic, clinical and biochemical data of laboratory confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV Open Reading Frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. Results 274 HEV-infected patients were included. Subtype assignment was possible for 179/218 viremic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin and alkaline phosphatase were found in clade efg infected patients in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors. It associated with a 2·1-fold higher risk of hospitalisation (95% CI=1·1–4·4, p-value (p)=0·034) and with a 68·2% fold higher peak of bilirubin levels (95% CI=13·3–149·9, p=0·010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0·0005) and a more pronounced liver necro-inflammatory activity (p = 0·022). Conclusions In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. Lay summary Hepatitis E virus genotype 3 infections are prevalent in high income countries and display a wide spectrum of clinical ...