Resting human B cells can be activated to proliferate in the presence of both polyclonal antibodies to immunoglobulin mu heavy chains and B-cell growth factor (BCGF). This process appears to be temporally controlled in that the initial activation of the B cells and their responsiveness to BCGF is carried out by polyclonal anti-mu-chain antibodies alone. We have used this system to investigate the role of the c-myc gene in the cell cycle of normal human peripheral blood B cells. Our results show that the polyclonal anti-mu-chain antibody-induced B-cell activation is accompanied by a specific induction of c-myc gene expression without promoting subsequent entry into the S phase unless BCGF is added. Monoclonal antibodies to either mu chain or the pan-B-cell antigen Bp35 also revealed a similar G0-to-G1 transition and activation of c-myc gene expression. However, unlike activation with polyclonal anti-mu-chain antibodies, cells stimulated with these monoclonal antibodies do not acquire responsiveness to BCGF. The results imply that additional inducible functions must be present to potentiate the myc-specific function in order for the B cells to acquire the capacity to proliferate in response to BCGF. These findings are discussed in relation to the origin of B-cell malignancies.