Two cationic proteins, a neutral phosphatase (NP‐tase) and a 70‐kD protein (p70) were isolated from Staphylococcus aureus by ion exchange chromatography. We compared their properties to those of the well established B cell mitogen of whole, fixed Staph. aureus strain Cowan I cells (SAC). Both purified proteins were able to induce immunoglobulin synthesis in PBMC cultures of healthy donors. NP‐tase and p70 also induced immunoglobulin synthesis of PBMC from those patienis with CVID who were also responsive to SAC plus IL‐2 stimulation. Immunoglobulin synthesis in response to NP‐tase and to p70 was time‐ and dose‐dependent and could be inhibited by addition of specific antibodies against the proteins. In contrast to SAC, no addition of exogenous IL‐2 was necessary to obtain maximal immunoglobulin synthesis induced by NP‐tase or p70. However, neither protein was able to induce immunoglobulin synthesis in B cell‐enriched cultures. High amounts of IL‐2 were found in supernatants of PBMC from healthy donors following stimulation with low concentrations of NP‐tase or p70, and this was associated with vigorous lymphocyte proliferation. Both proteins behave like typical antigens, and not like lectins or superantigens, since an NP‐tase‐stimulated T cell line showed an antigen‐specific, MHC‐restricted secondary response. In addition, no preferential T cell receptor Vβ chain usage was found with eight Vβ‐specific MoAb. It is likely that the two proteins induce antigen‐specific T cell activation, which is then followed by polyclonal activation of B cells via CD40 receptors and cytokine release