The molecules of the TNF superfamily and their receptors play crucial roles in the humoral immune response. In view of the powerful effects on germinal center (GC) B cell differentiation, the expression of these molecules should be tightly regulated. In this study, we have undertaken a detailed analysis of the regulation of CD27 expression following the differentiation of GC B cells supported by a follicular dendritic cell line. We show that CD27 is differentially expressed on B cell subpopulations at different stages of differentiation. Naive B cells are virtually negative but plasma cells generated in vivo are strongly positive for CD27 expression. GC B cells that exhibit a moderate expression of CD27 remarkably up-regulate the expression levels of this molecule when they differentiate into plasma cells, which is induced by IL-10. The up-regulation of CD27 expression correlates with that of CD38. Therefore, high expression of CD27 molecules emerges as a specific marker for plasma cells. Our results suggest an important role for CD27 in the differentiation of GC B cells into plasma cells. Evaluation of CD27 expression levels may be of a clinical significance in assessment of B cell maturation in immunocompromised patients.