Hepatitis B infections are a distinct clinical problem in hemodialysis patients. Naturally acquired antibodies from a prior hepatitis B virus infection generally are considered to be immunoprotective for subsequent infections. We describe a new-onset hepatitis B virus infection in a hemodialysis patient despite persistent protective levels of naturally acquired antibodies to hepatitis B surface antigen. This case emphasizes that the immune response to hepatitis B virus is complex and still poorly understood. Current recommended screening guidelines may be incomplete in addressing acute hepatitis B virus infections in hemodialysis patients. Aggressive vaccination strategies should be considered to maintain immunity in patients at high risk of seroconversion. Stricter surveillance and use of modern virus detection assays may be required to detect subtle infections and minimize the risk of transmission of hepatitis B virus in hemodialysis units.