A 51-year-old woman was admitted to the hospital with abdominal pain, jaundice, and transaminitis. The patient's laboratory results showed elevated liver enzymes, high antinuclear antibodies (ANA) titer, positive anti-smooth muscle antibody, and hypergammaglobulinemia. Given risk factors for HIV infection, an ADVIA Centaur® HIV Antigen/Antibody Combo assay was performed showing a reactive sample with a follow up HIV-1 nucleic acid test (NAT) proving to be negative. Following confirmation of autoimmune hepatitis type I via a liver biopsy, steroids were initiated and significant clinical improvement of symptoms as well as resolution in transaminitis were noted. Autoimmunity is the most likely causative factor in inducing a false positive reactive screening assay. It is important to recognize that cross-reactivity with autoimmune conditions and HIV specific proteins is a potential concern for false reactive samples.