Interleukin‐6 (IL‐6) induces B‐cell proliferation by binding to receptor complexes composed of a specific α‐receptor (gp80; CD126) and the signal transducing receptor subunit gp130 (CD130). Immediately after receptor complex activation, signal transducers and activators of transcription (STATs) 1 and 3 and the Src‐homology domain‐containing protein tyrosine phosphatase 2 (SHP2) are recruited to gp130 and subsequently tyrosine phosphorylated. The activated dimerized STATs translocate to the nucleus and bind to enhancer elements of IL‐6‐inducible genes. SHP2 acts as an adapter and links the Jak/STAT pathway to the Ras/Raf/MAPK cascade but it is also involved in signal attenuation. Whereas STAT3 activation appears to be crucial for all biological activities of IL‐6, the requirement of SHP2‐activation depends on the individual biological response analyzed. The requirement of SHP2 activation for the pre‐B cell (Ba/F3) proliferation has been reported previously [Fukada, T., Hibi, M., Yamanaka, Y., Takahashi‐Tezuka, M., Fujitani, Y., Yamaguchi, T., Nakajima, K. & Hirano, T. (1996) Immunity5, 449–460]. In contrast, we have recently demonstrated that the presence of a single STAT‐recruitment site within gp130 is sufficient for IL‐6‐ induced proliferation of Ba/F3 cells [Schmitz, J., Dahmen, H., Grimm, C., Gendo, C., Müller‐Newen, G., Heinrich, P.C. & Schaper, F. (2000) J. Immunol.164, 848–854]. To unravel this discrepancy we analyzed the IL‐6‐induced dose‐dependent proliferation of Ba/F3 cells mediated by receptor complexes lacking SHP2/SOCS3 recruitment sites. Surprisingly, pre‐B cells, after stimulation with low amounts of IL‐6, proliferate much more efficiently in the absence of the activated SHP2 than in the presence of the tyrosine phosphatase. Therefore, SHP2 activation appears to be relevant for IL‐6‐induced proliferation only after stimulation with very large amounts of IL‐6.