Myasthenia gravis (MG) is the leading paraneoplastic manifestation of thymomas and is probably related to the capacity of thymomas to mature and export potentially autoreactive T cells. Why some thymomas are MG associated (MG+) and others are not (MG−) has been unclear. We addressed this question by comparing the percentages of intratumorous naive mature CD45RA+ thymocytes in 9 MG(+) and in 13 MG(−) thymomas by fluorescence-activated cell sorting analysis. Our results show that intratumorous naive CD4 T cells were present in all MG(+) thymomas and in one MG(−) thymoma with the development of MG only 2 months after surgery. By contrast, the percentage of naive CD4⁺ T cells was significantly reduced in all 13 MG(−) thymomas (P < .0001). Alterations in intratumorous thymopoiesis were reflected by corresponding alterations of naive T-cell subset composition in the blood, in that only MG(−) patients had significantly decreased levels (P = .02) of naive CD4⁺ T cells compared with age- and sex-matched control persons. We conclude that paraneoplastic MG is highly associated with the efficiency of thymomas to produce and export naive CD4⁺T cells. The acquisition of the CD45RA⁺ phenotype on CD4⁺ T cells during terminal intratumorous thymopoiesis is associated with the presence of MG in most thymoma patients.