It is generally recognized that activation through membrane effector molecules such as CD40 or the B cell receptor (BCR) is mandatory to allow B cells to proliferate and differentiate into antibody (Ab)‐secreting cells in response to cytokines. We show here that purified tonsillar B cells can be stimulated directly by a cytokine combination to proliferate and secrete immunoglobulins when cultures are performed at high cell density. The contact‐mediated activation of B cells in this experimental system is strongly inhibited both by anti‐very late antigen (VLA)‐4 monoclonal Ab and by a peptide containing the LDV sequence specifically recognized by the α4 integrin binding site. These reagents also significantly suppressed the B cell responses elicited by engagement of the BCR or CD40. Our data reveal that memory B cells but not virgin or germinal center B cells are sensitive to the direct stimulatory effect of cytokines in high‐density cultures. Finally, we found that the dual expression of the α and β chains of VLA‐4 is a distinctive feature of the memory B cell population. Collectively, our findings support the notion that VLA‐4‐dependent homotypic B cell interactions can mediate a co‐stimulatory signal to human memory B cells and might participate in the B cell activation triggered through the BCR and CD40.