A case report of acute, massive, prolonged hepatitis related to secondary syphilis in a patient with undiagnosed HIV infection is described together with possible pathogenetic mechanisms. This is a rare occurrence in resource-rich countries in the era of antibiotics. The impaired immune response and the dysregulation of the cytokine network may have played a role in mediating this severe expression of HIV-associated secondary syphilis. An apparently unexplained acute hepatitis should deserve accurate screening for sexually transmitted diseases, including syphilis and HIV infection.