The 28-amino-acid neuropeptide, vasoactive intestinal peptide (VIP), is a potent mitogen during embryonic development and plays a vital role in brain growth. VIP is also mitogenic for tumor cells, including the human neuroblastoma (NMB). Northern blot analysis has revealed VIP mRNA transcripts in NMB. We now report VIP-like immunoreactivity within these neuroblastoma cells that increased during logarithmic growth and decreased after attaining confluency. About 10(6) seeded cells secreted 5-40 pg of VIP-like immunoreactivity into the medium. These results suggest an autocrine role for VIP in the regulation of neuroblastoma growth. A VIP hybrid antagonist (neurotensin6-11 VIP7-28) that has been shown to inhibit lung cancer proliferation was now tested for inhibition of neuroblastoma growth. Receptor binding studies indicated that the hybrid antagonist displaced [125I]-VIP binding in the neuroblastoma cells (EC50 = 5 x 10(-6)M). Furthermore, as measured by thymidine incorporation and by cell counts, the potent VIP hybrid antagonist inhibited neuroblastoma multiplication in a dose-dependent manner. In conclusion, VIP may be an important regulator of growth of nerve cell progenitors and of tumors derived from neuronal origin and intervening with VIP function may lead to improved treatment of cancer.