The B cell-specific antigen CD22 is a 130/140-Kd complex and is unique among human B cell antigens, since its surface expression is restricted to a subpopulation of Ig+ B cells. Here the function of the CD22 antigen was evaluated by using the mAb HD6, directed against one of the epitopes on the molecule. The HD6 antibody was constimulatory with anti-Ig in inducing small, dense tonsillar cells to proliferate; however, the antibody by itself was devoid of stimulatory activity. Anti-CD22 antibody also induced more anti-Ig-treated B cells to leave G0 and enter the G1 phase of the cell cycle. It also was constimulatory with low-m.w. BCGF and with an antibody to a 50-Kd polypeptide, Bp50, which mediates a BCGF-like activity. Results of kinetic experiments and analysis of different B cell fractions suggested that anti-CD22 acts during an early phase of B cell activation, probably by amplifying the anti-Ig signal. F(ab')2 fragments of anti-CD22 HD6 were as effective as the whole antibody in inducing augmentation of B cell proliferation, showing that the Fc portion of the molecule was not required for the activity. The results of these experiments, together with the intriguing distribution of the Bp 130/140 antigen in B cell ontogeny, suggest that this molecule plays an important role in the process that leads to B cell activation and proliferation.