The modulation of redox balance is able to drive different cell functions, from differentiation to proliferation. In a previous work, we showed that all-trans retinoic acid (ATRA) induced differentiation of SH-SY5Y neuroblastoma (NB) cells through the generation of reactive oxygen species (ROS) [Nitti et al Cell Signal 2010]. However, ATRA-differentiated NB cells resulted more sensitive to the further unbalance of redox state in comparison with undifferentiated ones, as shown in response to glycoxydative stress [Nitti et al Neurosci Letters 2007]. Heme oxygenase 1 (HO-1), induced by the transcription factor Nrf2, plays a crucial role in cell adaptation to oxidative stress through the generation of bilirubin, ferritin and carbon monoxide with antioxidant and anti-inflammatory properties. In this work, focusing on Nrf2/HO-1 axis, we investigated the ability of undifferentiated and ATRA-differentiated NB cells to balance oxidative stress. SH-SY5Y exposure to 100-500 μM H2O2 decreased cell viability significantly more in ATRA- differentiated cells than in the undifferentiated ones. The expression of GCLM and GCLC, key enzymes in the synthesis of GSH, was not modified by H2O2 treatment in any condition. However, after H2O2 treatment heme oxygenase 1 (HO-1) expression and Nrf2 binding to HO-1 promoter were significantly reduced in differentiated cells in comparison to the undifferentiated ones. In addition, exposure to bilirubin prevented cell death induced by H2O2 in differentiated cells. Our data show that retinoic acid-dependent differentiation impairs Nrf2-dependent HO-1 induction in response to H2O2 and, by reducing the availability of endogenous bilirubin, decreases cell adaption to oxidative stress. Nrf2 nuclear translocation and post-transcriptional modifications are under investigation. Grant from MIUR-PRIN20125S38FA and Genoa University.