BALB/c mice were injected intravenously with three different monoclonal antibodies (mAbs) specific for complement receptor 1 (CR1). Two of the mAbs crossreacted with CR2. 24 h later, the mice were immunized with horse erythrocytes or keyhole limpet hemocyanin (KLH), and the primary antibody response was measured. One of the anti-CR antibodies, 7G6, suppressed greater than 99% of the direct plaque-forming cell response against horse red blood cells (HRBC). The same antibody markedly suppressed the serum antibody responses to both HRBC and KLH. To be optimally suppressive, the mAb had to be injected before suboptimal concentrations of antigen. The other two complement receptor-specific antibodies had very moderate, if any, effects on the antibody response. 7G6 was able to downregulate CR1 and CR2 on the surface of B cells and, in addition, to inhibit rosette formation with C3d-coated sheep erythrocytes (EC3d). One of the antibodies with a weak effect downregulated only CR1. The other downregulated both CR1 and CR2, although not as efficiently as 7G6, and was unable to inhibit EC3d rosette formation. We conclude that the reason 7G6 is outstanding in its suppressive capacity is that it is the only mAb tested that functionally blocks CR2. The data suggest that CR2 is of crucial importance in the initiation of a normal antibody response to physiological concentrations of antigen.