Abstract By using conditional, B cell-restricted MHC-II-deficient mice (IA-B mice), we previously showed that antigen-specific memory B cells could be established but they then lost MHC-II expression due to ongoing cd19Cre-mediated deletion of the conditional iab allele, without significant loss in memory cell number. In this study, we examined whether or not MHC-II deficient memory B cells are functionally competent to differentiate into plasma cells. IA-B mice carrying a 4-hydroxy-3-nitro-phenyl-acetyl (NP) hapten-specific VH transgene (QM) were immunized with NP-coupled chicken gamma globulin plus alum. QM/IA-B mice generated NP+IgG+ memory B cells (~0.1% of total spleen cells), which subsequently lost MHC-II during maintenance. When cultured in the presence of 3T3 feeder cells with cytokines and various stimuli, both MHC-II(+) and MHC-II(−) NP+ memory B cells purified from QM/IA-B mice produced anti-NP IgG antibody upon LPS stimulation. However, anti-NP IgG production of MHC-II(−) NP+ memory B cells upon polyvalent B cell receptor stimulation with NP−Ficoll was significantly reduced compared to that of MHC-II(+) NP+ memory B cells. These results suggest that expression of MHC-II on memory B cells is required for maintenance of their capacity to differentiate into plasma cells in response to antigen stimulation. This work was supported by NIAMS AR052470 (M.S.) and NIAID AI47379 (P.A.K.).