Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM‐deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSM‐deficient mice. Apoptotic cells accumulated in the thymus of OSM‐deficient mice, and the administration of dexamethasone in young OSM‐deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.