We have previously shown that immunization with SIV-, SHIV-, or HA (influenza hemagglutinin)-virus-like particles (VLPs) elicits a strong humoral immune response in mice. However, little is known about the action VLPs exert on immune effector cells, including B cells. In this study, we found that all three types of VLPs could directly bind and activate B cells in vitro. VLPs stimulated the proliferation of B220+IgM+CD43−CD5− B2 cells and their differentiation to plasma cells that preferentially produce IgG2a antibodies. Up-regulation of Blimp-1, XBP-1, IRF4, and AID genes, which are responsible for class-switch recombination and somatic hypermutation, was observed in VLP-activated B2 cells. Stimulation of naïve splenocytes with VLPs led to a high expression of IL-12, RANTES and MIP, the cytokine milieu that favors B cell differentiation into IgG2a secreting cells. VLP immunization of C57BL/6 mice corroborated our in vitro data showing enlarged germinal centers and expanded conventional B2 cells, but no enlarged marginal zone B1 cells, in the spleen. Enhanced antigen-specific plasma cell formation, antibody production, and IgG2a class switching were found in VLP-immunized groups. The current study details the interaction between VLPs and B cells which result in preferential IgG2a antibody production following VLP immunization.