The role of NF-κB in the Ewing’s sarcoma family of tumours (ESFT) and their response to fenretinide has been investigated. Basal levels of phosphorylated NF-κB were low in all ESFT cells. BAY 11-7082 decreased cell viability, which was accompanied by caspase-3 cleavage. This was independent of the increase in reactive oxygen species, p38^MAPK phosphorylation and expression of NF-κB target proteins. NF-κB knockdown did not induce death under normal growth conditions, but did reduce TNFα-dependent cell survival. Fenretinide-induced apoptosis was independent of NF-κB. BAY 11-7082-induced cell death through an NF-κB-independent mechanism and enhanced cell death when combined with fenretinide.