BackgroundHepatitis Delta virus (HDV) Infection has a worldwide distribution, with approximately 20 millions infected persons. Interferon (IFN) is the only approved drug for the treatment of HDV infection which is still a difficult to treat disease. Objectives To report a successful treatment of a patient with a chronic severe hepatitis Delta using combination therapy with Pegylated interferon (PegIFN), Tenofovir disoproxil fumarate (TDF) and Emtricitabine (FTC). Study Design The patient, a 47 years -old male patient, originating from Dagestan (East Asia), suffered of chronic hepatitis Delta infection. The patient was HBsAg, HBeAg, and anti-Delta Ab (IgG) positive. Serum HBV-DNA level was elevated (more than 9 logUI/mL). Serum HDV-RNA level was up to 5.6 log (copies/ml). Genotypes HBV/D and HDV-1 were demonstrated. The liver histology revealed chronic active hepatitis (Metavir score: A2F2). The treatment was started with PegIFN (180 μg/week) for two months and then TDF (300 mg/day) (combined later with FTC) was added. Results Sustained response was obtained after 10 months of treatment and was accompanied by the clearance of serum hepatitis B virus surface antigen with seroconversion to anti-HBs. Conclusion This case report suggests that Delta infection may co-exist with high replicative HBV infection and that combination therapy with PegIFN and nucleoside/tide analogues seems to be more effective than IFN alone. Given that only a single case is reported, further studies including more patients are warranted.