The Ewing's sarcoma family of tumours (ESFT) are small round cell tumours characterized by the non-random EWS-ETS gene rearrangements. We have previously demonstrated that ESFT are highly sensitive to fenretinide-induced death, effected in part through a reactive oxygen species (ROS)-dependent pathway. Here, we demonstrate for the first time that the sensitivity of ESFT cells to fenretinide-induced cell death is decreased following downregulation of the oncogenic fusion protein EWS-Fli1; siRNA targeting EWS-Fli1 attenuated fenretinide-induced cell death in cell lines expressing EWS-Fli1, but not EWS-ERG. This decrease in cell death was independent of the level of ROS produced following exposure to fenretinide, but was effected through EWS-Fli1-dependent modulation of p38(MAPK) activity. Furthermore, inhibition of p38(MAPK) activity and knockdown of EWS-Fli1 reduced fenretinide-induced mitochondrial permeabilization, cytochrome c release, caspase and PARP cleavage, consistent with the hypothesis that p38(MAPK) is critical for activation of the death cascade by fenretinide in ESFT cells. These data demonstrate that expression of EWS-Fli1 enhances fenretinide-induced cell death in ESFT and that this is effected at least in part through modulation of p38(MAPK) activity.