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Background/Objectives: Hepatitis E virus (HEV) infection is an increasingly recognized cause of acute hepatitis in Europe, but short-term in-hospital laboratory dynamics remain insufficiently described in hospitalized cohorts. We aimed to characterize admission biochemical abnormalities and paired admission-to-discharge laboratory changes in hospitalized patients with acute hepatitis E from Craiova, Romania, with exploratory sex- and age-stratified analyses. Methods: We conducted a single-center retrospective observational study including 40 consecutive hospitalized patients with acute hepatitis E during 2024–2025. Admission and discharge laboratory values were compared at the within-patient level, and exploratory subgroup analyses by sex and age class were performed. Given the limited sample size, multivariable analyses were restricted to parsimonious age-adjusted models for selected endpoints. Results: The cohort comprised 22 females (55%) and 18 males (45%), with a mean age of 53.05 ± 21.44 years; two in-hospital deaths occurred. At admission, marked transaminase elevation and frequent hyperbilirubinemia were observed, with 70% of patients having total bilirubin ≥ 2 mg/dL and 40% ≥ 10 mg/dL. During hospitalization, ALT and AST declined markedly, whereas total and direct bilirubin improved more modestly, indicating slower resolution of jaundice/cholestatic abnormalities. Platelets increased, while prothrombin index changes were heterogeneous. Male patients had higher bilirubin values at admission and discharge and more frequent clinically relevant hyperbilirubinemia thresholds; however, these findings should be interpreted cautiously given the small sample size, the retrospective design, and the absence of standardized clinical confounders and mechanistic data. Exploratory age-stratified analyses did not identify robust differences after multiplicity control. Conclusions: In hospitalized hepatitis E, hepatocellular injury markers improved rapidly during hospitalization, whereas cholestatic abnormalities resolved more slowly and often remained clinically relevant at discharge. The observed sex-related cholestatic pattern should be considered exploratory and requires confirmation in larger studies with standardized clinical covariates and longer follow-up. These findings support closer monitoring of bilirubin trajectories at discharge, particularly in male patients, and highlight the need for integrating laboratory dynamics into short-term clinical assessment of hospitalized HEV cases.