Protein A (PA) of Staphylococcus aureus is known as an immunomodulator. In a search of the molecular mechanism(s) of PA-induced immunocyte potentiation, we found dose-dependent binding of PA (0.01 to 100 μg/ml PA) to the mice splenic lymphocytes. Interestingly, treatment of 1 μg PA/20 g mice increased the splenic lymphocyte number ~5-fold over control but at a 10-μg dose the cell number was decreased compared with a 1-μg dose. Flow cytometric analysis of cell-cycle phase distribution of nuclear DNA in splenic lymphocytes showed that at a 1-μg dose, PA shifted the cell-cycle phases from G0/G1 to S and G2/M supporting the pro-proliferative role of PA. In contrast, the same inducer increased the sub-G1 cell population at a 10-μg dose indicating the breakdown of cellular DNA. These findings were supported by DNA ladder formation and nuclear breakdown at this higher dose. Further studies revealed that at a 1-μg dose, the level of the pro-proliferative/anti-apoptotic protein bcl-2 was increased in splenic lymphocytes whereas at a 10-μg dose it showed a decreasing trend. In contrast, concentrations of proapoptotic proteins, p53 and bax, were increased at a 10-μg dose. A search of the mechanism(s) of such differential action of PA at these two doses revealed that the lower dose of PA upregulated the production of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) to the extent which has already been reported by our laboratory to be beneficial to the host. However, at a larger dose, much higher release of TNF-α and interleukin-2 (IL-2) may account for the apoptosis of splenic cells. All these findings indicated that the cross-talk between all these pro- and anti-apoptotic factors may contribute to maintain a balance between growth and death of cells and may be one of the important factors deciding whether a cell would follow a proliferative pathway or an apoptotic pathway.