Mature human B lymphocytes perform many functions including antibody secretion, Ag presentation, preservation of memory for Ag, and lymphokine secretion. Individual resting B cells receive multiple sequential signals that determine the function(s) that will be performed by those cells. Activation signals such as Ag or Staphylococcus aureus Cowan I (Sac) stimulate overlapping but different subpopulations of B cells. After activation, B cells may be induced to proliferate by a variety of B cell growth factors (BCGF) including IL-2, IL-4, TNF-alpha, low molecular weight BCGF (LMW-BCGF), and high molecular weight BCGF (HMW-BCGF). Little information exists to explain why so many different BCGFs are involved with human B cell proliferation. The current studies were designed to examine the role HMW-BCGF plays in selecting B cells for particular functions. HMW-BCGF but not LMW-BCGF was found to inhibit Ig secretion when it was included in culture with Sac-activated B cells and B cell differentiation factors (BCDFs) including IL-6. Sorting resting B lymphocytes into surface IgD+ and IgD- populations and then stimulating each population with anti-mu revealed that the cells most responsive to HMW-BCGF resided in the surface IgD- sorted population. Sorting activated B lymphocytes into BA5 (HMW-BCGFR)+ and BA5- populations revealed that BA5+ B cells stimulated with BCDF (in the absence of HMW-BCGF) produced predominantly IgG, whereas the BA5- population produced both IgG and IgM. Finally, expansion of peripheral B cells from tetanus toxoid-immunized donors with either HMW-BCGF or LMW-BCGF revealed that the HMW-BCGF-expanded population produced predominantly IgG tetanus-specific antibody in the presence of BCDF (in the absence of HMW-BCGF), whereas the LMW-BCGF-expanded population produced IgM much greater than IgG tetanus-specific antibody. Thus, HMW-BCGF may function to expand a subpopulation of B cells for memory B cell functions.