Neuroblastomas are characterized by defects in tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induced apoptosis, especially down-regulation and methylation of Caspase-8 (CASP8). This defect is associated with amplification of N-myc. However, N-myc has also been implicated in induction of apoptosis, especially activation of CASP9 mediated apoptosis. Here we found that ectopic N-myc expression induces TRAIL susceptibility, both by CASP8 and CASP9 mediated apoptosis. N-myc did not modify CASP8 expression and methylation. CASP8 defects therefore represent an independent event in neuroblastoma, counteracting the N-myc induced susceptibility to apoptosis. Analysis of the CASP9 mediated route in a series of neuroblastoma cell lines, we found normal expression and no aberrant methylation of four apoptotic intermediates, including CASP9 itself.