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.