We aimed to characterize the contribution of hepatitis E virus (HEV) in perpetuating the cytokine-mediated inflammatory setting related to liver damage in the context of obesity. Herein, serum samples from patients with liver disease were retrospectively analyzed and categorized as normal-weight patients (NW), overweight patients (OW), obese patients (ObP), and high alcohol consumer patients (HAC), and biochemical, anthropometrical, and transient elastography measurements were obtained. The positivity for immunoglobulin M (IgM) and immunoglobulin G (IgG) anti-HEV antibodies in samples was determined by enzyme-linked immunosorbent assay. Available samples from ObP were tested by reverse transcription-nested polymerase chain reaction for the presence of HEV-RNA. Cytokine profile in the serum of ObP was identified using a multiplexed immune assay. Globally, the highest frequency of IgG anti-HEV was found in ObP (57.5%), followed by HAC (20%), OW (15%), and NW (7.5%). A strong association between HEV serology and obesity was found (odds ratio = 4.21, confidence interval = 1.91.9.27) with a cutoff of 29.3 kg/m2 (area under curve [AUC] = 0-66; p = 0.003) and, a 23.7% of available samples of ObP provided amplification of HEV genome. Cytokine analysis revealed significantly higher levels of proinflammatory cytokines (interleukin [IL]-12, interferon [IFN]-γ, and IL-1β) in IgG anti-HEV-positive ObP than in IgG anti-HEV-negative ObP. Moreover, a high proportion of patients with positive serology showed advanced liver damage. In conclusion, the high percentage of anti-HEV antibodies and viral RNA detection in the setting of an excess of fat, along with an associated proinflammatory cytokine profile found in IgG anti-HEV-positive ObP with more severe liver disease, support an interplay between HEV and obesity.