Hepatitis B virus (HBV) causes severe liver disease by establishing persistent infection in human hepatocytes. Current medications suppress viral replication but cannot eliminate the virus from infected cells. Efforts are focused on modulating intracellular immunity to develop new therapies targeting the major genomic form of HBV, known as covalently closed circular DNA (cccDNA). One potential approach involves utilizing cytidine deaminases APOBEC/AID, which have the ability to mutate and degrade HBV cccDNA. Our study reveals a novel evasion strategy used by HBV to counteract APOBEC/AID immunity and maintain a viral reservoir within the nuclei of infected cells by saturating these enzymes with relaxed circular DNA (rcDNA), the primary target of cytidine deaminases. Reducing rcDNA levels by siRNA or lamivudine or by using transcriptionally silenced cccDNA enhances cccDNA deamination by major APOBEC/AID enzymes. We also demonstrate severe deamination of the host genome by APOBEC3A, APOBEC3B, and AID upon viral suppression by siRNA or lamivudine, indicating that APOBEC/AID cannot be regarded as safe for antiviral treatment in cells with low HBV replication levels. Finally, we show that APOBEC3C and APOBEC3H can improve anti-HBV activity of siRNA therapeutics but do not affect cccDNA deamination. Off-site deamination for these factors was not detected at selected cancer-related genes.