Class II antigens of the major histocompatibility complex (MHC) have a clear role in restricting cellular interactions and presenting processed antigen to T cells. In addition, a fundamental role for class II antigens in cellular activation has been suggested, following studies which demonstrated that class II antigen binding altered signal transduction in various cell types. We have investigated the role of HLA class II antigens in signal transduction of human B lymphocytes. Resting B lymphocytes proliferate in response to immobilized anti-class II antibodies and intracellular free calcium is increased following cross-linking of anti-class II antibodies. The two dimensional PAGE pattern of resting B lymphocytes was examined and differences were noted after stimulation with either anti-class II antibodies, anti-IgM or PMA. The 2D PAGE pattern following stimulation with anti-class II antibodies was not identical to that observed following stimulation with either anti-IgM or PMA. These data suggest that the activation of B-Go via the class II antigens shares part of the pathway of anti-IgM induced activation but does not follow an identical pathway.