Background <p>Hepatitis delta virus (HDV) infection occurs in patients with underlying hepatitis B virus (HBV) infection and is associated with more rapid liver disease progression. This study aimed to describe the epidemiology of HDV, describe HDV management, and compare disease progression among patients with HDV vs. HBV mono-infection in Israel.</p> Methods <p>This retrospective cohort study used anonymized data from Maccabi Healthcare Services. HDV prevalence and incidence were calculated among adults in 2010–2021 (latest decade, PCR test available in the database). HDV management and progression to a more advanced disease state and/or death (composite outcome) were examined in 2005–2021 (maximize follow up, antibody test available in the database). Disease progression post-index compared among HDV (index = earliest diagnosis or HDV-positive laboratory test) vs. HBV mono-infection (index = earliest HDV-negative test) by baseline disease state using Kaplan-Meier and Cox analysis.</p> Results <p>From 2010 to 2021, average annual HDV prevalence and incidence rates among patients with HBV (general population) were 2.3% (12.4/100,000) and 0.11% (0.59/100,000), respectively. From 2005 to 2021, patients with HDV (<i>N</i> = 168) vs. HBV mono-infection (<i>N</i> = 2,580) had lower socioeconomic status and higher baseline prevalence rates for HIV, HCV PCR positive, diagnosed drug dependence, and alcohol abuse. Risk of disease progression was higher among patients with HDV vs. HBV mono-infection (adjusted HR = 4.4, <i>P</i> &lt; 0.001).</p> Conclusions <p>HDV prevalence among adults with HBV remained steady. Patients with HDV vs. HBV mono-infection had higher risk of progression to a more advanced liver disease state and/or death. The results of this study underscore a need for earlier identification of HDV infection, as well as more effective strategies for the diagnosis and treatment of HDV to mitigate future disease progression.</p> Trial registration <p>Not applicable.</p>