Background <p>Hepatitis E virus (HEV) infection typically presents as a self-limiting acute hepatitis, but a subset of patients may progress to severe hepatitis, with potential progression to liver failure or even death. Identifying clinical predictors of such severe progression is essential for early risk stratification and timely intervention. This study aimed to investigate independent risk factors associated with severe outcomes in acute HEV infection.</p> Methods <p>A retrospective analysis was conducted on 146 hospitalized patients diagnosed with acute HEV infection at Shanghai Ninth People's Hospital from January 2017 to May 2025. Demographic data, laboratory parameters, and clinical outcomes were systematically collected. Correlation analysis and logistic regression models were applied to identify independent risk factors for disease severity.</p> Results <p>45 patients (30.8%) progressed to severe hepatitis. Increasing age, elevated white blood count(WBC), decreased hemoglobin(HGB) and reduced CD4⁺ T cell counts were associated with higher risk of severe outcomes. Multivariate logistic regression identified elevated WBC count (OR=1.226, 95% CI:1.006–1.495, p=0.044) and decreased HGB level (OR=0.948, 95% CI:0.915–0.983, p=0.004) as independent risk factors. Further, WBC ≥9×10⁹/L and HGB &lt;90 g/L were significantly associated with severe outcomes. The protective effect of elevated HGB was more pronounced in male patients (P_interaction = 0.003) and those with underlying liver disease (P_interaction = 0.026)</p> Conclusion <p>Elevated WBC count and reduced HGB level are critical indicators for predicting severe hepatitis outcomes in patients with acute HEV infection. Monitoring these specific blood indicators can assist clinicians in identifying high–risk patients and taking preemptive measures to halt disease progression.</p> Clinical trial number <p>Not applicable.</p>