Hepatitis B core antibody (anti-HBc) is considered the most sensitive serological marker for history of hepatitis B virus (HBV) infection. In a subset of anti-HBc carriers, anti-HBc is present in the absence of hepatitis B surface antigen and hepatitis B surface antibody-a serological pattern known as "isolated anti-HBc" (IAHBc). IAHBc has been of clinical interest over the past several years, with growing data to suggest its role as a serological marker for occult HBV infection (OBI). This article reviews the clinical significance and association of IAHBc with hepatitis C virus (HCV) co-infection, risk of HBV reactivation during direct-acting antiviral therapy for HCV as well as immune suppression, and development of hepatocellular carcinoma (HCC). Hepatitis B core-related antigen is also highlighted as an emerging laboratory assay that may identify OBI and predict HCC development in non-cirrhotic patients receiving nucleoside/nucleotide analog therapy.