The repertoire of autoantibodies found in cancer patients partly overlaps with that typical of patients with autoimmune diseases. Beside the biochemical and immunological properties of the target antigens and their altered expression in tumor tissues, the intratumoral inflammatory context can play a key role in the induction of autoimmune disease-associated autoantibodies in cancer patients. Furthermore, the impact of such antibodies on cancer growth and progression can be deeply influenced by the interplay with inflammation. The characterization of the spontaneous humoral responses occurring in cancer patients, of the mechanisms that trigger and sustain the autoantibody response and of the biological effects of such autoantibodies may help the rational design of anti-cancer immunotherapeutic protocols.