Myasthenia gravis (MG) is mediated by autoantibodies to the acetylcholine receptor (AChR), expressed in muscle and rare thymic myoid cells. Most early‐onset cases show thymic lymph node‐type infiltrates, including pre‐activated plasma cells spontaneously producing anti‐AChR antibodies. Since these are not evident in the associated thymomas found in another 10% of MG patients, AChR‐specific B cells must be autosensitized elsewhere. Unexpectedly, at diagnosis, >70% of MG/thymoma patients also have high‐titer neutralizing autoantibodies to IFN‐α, and >50% to IL‐12; moreover, titers increase strikingly if the thymomas recur, indicating a closer tumor relationship than for anti‐AChR. To investigate this, we have measured autoantibody production by cells cultured from thymomas, any available thymic remnants and blood, with or without the B cell stimulant pokeweed mitogen (PWM). To check autoantibody specificity and clonal origins, we isolated Fabs from two combinatorial libraries from producer thymus/thymoma cells. Surprisingly, thymoma cells spontaneously produced antibodies to IFN‐α and/or IL‐12 in >40% of seropositive cases, showing typical plasma cell behavior, whereas they produced anti‐AChR only after PWM stimulation. We isolated 15 combinatorial Fabs to IFN‐α (versus only one to AChR). Their strong binding in radio‐immunoprecipitation and Western blots implies high affinities. The four Fabs tested neutralized anti‐viral actions of IFN‐α. The diverse V genes clearly showed ongoing antigen‐driven selection. These results imply pre‐activation in situ by native IFN‐α/IL‐12 expressed within a ‘dangerous’ tumor microenvironment. With these molecules, it should be easier to identify provoking cell type(s) that may give novel additional clues to autoimmunization against T‐cell epitopes from the more complex AChR.