Antibody neutralization would be a major way to prevent HIV infection and disease progression, but the complex relationship between host and pathogen makes tough to achieve this target through immunogens based on viral envelope proteins. Autoimmunity has been associated to bacterial and viral diseases, as a consequence of inflammatory response to pathogens; it may eventually lead to harm host cells and organs. However, autoimmune-like responses have also been observed in HIV-infected patients, raising many questions about their clinical significance. Recent studies have elucidated both similarities and differences between anti-self responses in HIV infection and autoimmune diseases, identifying new molecular players that might enhance immune protection to HIV and/or modulate the clinical progression of the established infection. This paper will present the current knowledge on auto-antibodies observed in HIV infection, their putative mechanisms of generation and their possible implications for immune therapy.