Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38MAPK, in contrast to the transient activation of p38 MAPK associated with bFGF-induced cell proliferation. Stem cell factor-induced survival of TC-32 cells was also associated with transient activation of p38MAPK. Inhibition of p38MAPK by SB202190 and p38MAPK small interfering RNA reduces bFGF-induced death in TC-32 cells, consistent with the hypothesis that activation of p38MAPK is essential for induction of death by bFGF. This appears to be dependent on sustained activation of p38MAPK demonstrated by inhibition of bFGF-induced cell death following addition of SB202190 to TC-32 cells 5 min after exposure to bFGF (20 ng/ml) and activation of p38MAPK. Prolonged activation of p38MAPK is accompanied by a rapid and sustained phosphorylation of Ras and ERK; inhibition of ERK phosphorylation using the MEK-1 inhibitor PD98059 rescued ∼30% of cells from bFGF-induced death suggesting ERK plays a secondary role in the induction of death. This hypothesis is supported by observations in the A673 cell line; bFGF induced sustained activation of ERK and transient activation of p38MAPK, which was not associated with cell death. These data demonstrate that sustained activation of p38MAPK is essential for activation of the death cascade following exposure of Ewing's sarcoma family of tumors cells to bFGF and provide evidence that activation of p38MAPK results in an up-regulation of the death receptor p75NTR.