Abstract A relationship between cancer and autoimmune rheumatic diseases has been observed for many decades, although the relevance of, and mechanisms underlying this association remain unclear. Investigating this relationship has been extremely challenging, due to (i) the striking heterogeneity of the rheumatic diseases, (ii) the use of numerous pharmacologic agents which can be associated with cancer, (iii) the kinetic heterogeneity of cancer onset (some cancers precede the rheumatic disease; most follow diagnosis of cancer, but over a period which can vary from 0-25 years); and (iv) the large number of tumor types associated with rheumatic disease. Although >80% of rheumatic disease patients do not have any associated cancer, a striking temporal clustering of the onset of cancer and autoimmune rheumatic disease has been observed. This is true for Dermatomyositis and Polymyositis, where most cancers are diagnosed -1 to +1 years around the onset of the rheumatic syndrome. Cancer is diagnosed in ∼15% of all patients with DM (mostly adenocarcinomas). Interestingly, myositis autoantigens are expressed at very low levels in most normal tissues, but at increased levels in both tumors and inflamed muscle, where autoantigen expression is localized to regenerating muscle cells. Similar observations have been made in other rheumatic diseases including scleroderma. The available data suggest a model where autoantigen expression and inflammation in the tumor initiates a humoral and cellular immune response to autoantigens. In the setting of injury to a normal tissue (e.g. muscle), the precursors which differentiate to repair the injury express the same antigens, and become the target of the ongoing immune response, and drive tissue damage in a feedforward loop. Citation Format: Antony Rosen, Livia Casciola-Rosen. Autoimmune rheumatic diseases and cancer: Not just chance? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN01-03.