Efforts to define the stromal architecture of thymic tissues of normal mice have used a panel of monoclonal antibodies (MTS series) to examine the localization of cell subtypes, including reagents that define thymic epithelial and stromal elements. Recent work with these MTS mAbs disclosed significant abnormalities in the thymic cortex of New Zealand mice including the appearance of medullary type epithelial cells in the cortical areas and the presence of epithelial free spaces or ‘cortical holes’. To determine whether such abnormalities are unique to NZB mice or are found in other models of murine lupus, we examined the thymi of MRL/MP-lpr/lprBXSB/MpJYaa, C3H/HeJ-gld/gldand C57BL/6 control mice. Thymi from all models of murine lupus showed dramatic alterations in the thymic microarchitecture. For example, staining with MTS10, a mAb which is specific for subcapsular and medullary epithelia, was decreased in the subcapsular and medullary regions. Moreover, there was increased staining in the thymic cortex, suggesting an abnormality in the localization of MTS10-reactive cells. Moreover, all three murine lupus strains demonstrated ‘cortical holes’ or cortical epithelial cell-free regions. By using MTS33, MTS35 and flow cytometry, both C3H/gldand BXSB/Yaa, but not MRL/lprmice, showed decreased cortical thymocyte frequencies. Possible defects in the maturation of double-positive thymocytes to single-positive status in C3H/gldmice is implied by abnormally high levels of double-positive cells and low levels of single-positive cells. Finally, MRL/lprthymocytes had lowered frequencies of CD3⁻4⁺8⁺and increased levels of TCR-α/β^highcells. Overall, these data suggest the need to define the functional implications of the dramatic changes within the thymic cortex in murine lupus.