To analyze the role of interleukin 4 (IL4, BSF-1) during primary activation of resting (high-density) murine CD8 T cells, a model system was used which bypasses antigen-presenting cells by the use of anti-T3 monoclonal antibodies immobilized on Sepharose beads. In high, but not in low cell density cultures, IL4 alone induced cell growth. In low cell density cultures, further to T3 cross-linking a soluble macrophage product was required as co-stimulator to induce sensitivity to IL4. This co-stimulator activity was unrelated to recombinant (r)IL1, rIL6 and rTNF-alpha (tumor necrosis factor alpha). In primary CD8 T cell responses rIL4-driven growth was about half of that induced by rIL2, and not inhibitable by anti-IL2 receptor antibodies. Higher concentrations of IL4 down-regulated cell proliferation. In the course of IL4-driven growth, the proliferating cells acquired sensitivity to the growth-promoting effect of IL2. Activated CD4 or CD8 T cells were found to be equally sensitive to the IL4 and IL2-driven growth pathway. Taken together, these results define a physiologic role of IL4 as growth factor during primary activation of resting CD8 T cells and thus extend the spectrum of target cells for IL4.