CD40 is a TNF receptor superfamily (TNRSF-5) member that initiates important signaling pathways mediating cell growth, survival and differentiation in B-lymphocytes. Although CD40 has been extensively studied as a plasma membrane-associated growth factor receptor, we demonstrate here that CD40 is present not only in the plasma membrane and cytoplasm, but also in the nucleus of normal and neoplastic B-lymphoid cells. Confocal microscopy showed that transfected CD40-GFP fusion-protein entered B-cell nuclei. The CD40 protein contains a nuclear localization signal (NLS) sequence, that when mutated, blocks entry of CD40 into the nucleus through the classic karyopherins (Importins-a/sspathway). Nuclear fractionation studies revealed the presence of CD40 protein in the nucleoplasm fraction of activated B cells, and chromatin immunoprecipitation assays demonstrated that CD40 binds to and stimulates the BLyS/BAFF promoter. CD40, another TNF family member, involved in cell survival in the B cell linkage, like other nuclear growth factor receptors, appears to be a transcriptional regulator and is likely to play a larger and more complex role than previously demonstrated, in regulating essential growth and survival pathways in B-lymphocytes.