Expression of trk family genes are prognostic indicators of neuroblastoma. However, the functional role of neurotrophins and their receptors in neuroblastomas in vivo is still unclear. We studied the expression of neurotrophin receptors (trk-A, trk-B, trk-C) and their responsiveness to neurotrophins (NGF, BDNF, NT-3) in 25 human neuroblastomas using a primary culture system. The tumours in early stages and stage 4s responded to both NGF and NT-3, but not to BDNF, by surviving and differentiating terminally and the responsiveness was correlated with high levels of trk-A, especially the neuronal isoform. However, in many advanced stage tumours, the expression of trk-A was down-regulated and the response pattern to neurotrophins was diverse, without showing terminal differentiation. Interestingly, a stage 4 tumour with MYCN amplification which expressed high level of neuronal trk-A was dependent on nerve growth factor (NGF) for both survival and differentiation in primary culture. The results suggest that the NGF/trk-A signalling may be the main regulatory pathway for differentiation and survival of neuroblastoma in vivo and that trk-A overexpression may overcome aggressiveness, even of the tumour with MYCN amplification.