AbstractBackgroundNon‐alcoholic fatty liver disease (NAFLD) has become the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Although various genetic and lifestyle‐related risk factors have been identified, its pathophysiology has not yet been fully unravelled. While acute EBV infection in the setting of infectious mononucleosis can lead to acute hepatitis, the long‐term hepatic sequelae of infectious mononucleosis are still poorly understood.MethodsThis retrospective cohort study included 13,859 patients with and 13,859 matched individuals without infectious mononucleosis from the Disease Analyzer database (IQVIA). Multivariable Cox regression analyses were used to evaluate the association between infectious mononucleosis and NAFLD.ResultsWithin 10 years of the index date, 2.64% of patients with infectious mononucleosis and 1.78% of individuals without infectious mononucleosis had been diagnosed with NAFLD (p < .001). The incidence of NAFLD was 263.9 cases per 100,000 person‐years among individuals with infectious mononucleosis and 164.5 cases per 100,000 person‐years among those without. Multivariable regression analyses indicated that infectious mononucleosis was significantly associated with the incidence of NAFLD (HR: 1.73) both among women (HR: 1.73) and among men (HR: 1.70). In age‐stratified analyses, the association between infectious mononucleosis and NAFLD was most pronounced for the groups aged between 41 and 50 years (HR: 2.94) and >50 years (HR: 2.68).ConclusionInfectious mononucleosis is significantly associated with the incidence of NAFLD in a large cohort from Germany. These findings suggest a pathophysiological involvement of EBV in the development of NAFLD and could stimulate research efforts to better understand the pathophysiology of this emerging global medical burden.