Neuroblastoma is the second most common pediatric malignancy, characterized by a high rate of unexplained spontaneous remissions. Much progress has been made in understanding neuroblastoma differentiation triggered by certain agents such as retinoic acid. However, little is known about the signalling pathways that lead to differentiation of neuroblastoma cells due to serum withdrawal. We found that in Neuro2a neuroblastoma cells, EGFR, ERK1/2 and Akt showed increased phosphorylation after serum withdrawal, and that the activation of EGFR was necessary for the activation of Akt and ERK1/2. Inhibition of EGFR, ERK1/2 and PI3K blocked neuroblastoma differentiation after serum withdrawal. Interestingly, addition of high-density lipoprotein (HDL) abrogated serum-withdrawal induced neuroblastoma differentiation, as well as the activation of EGFR. Our results demonstrate a novel role for serum-derived lipoproteins in the control of receptor tyrosine kinase activity.