Insulin-like growth factor II (IGF-II) and mannose 6-phosphate (man-6-P) bind to distinct sites on the same receptor. In the present study, we examined the effects of man-6-P on the growth promoting effects of IGF-II on SH-SY5Y cultured human neuroblastoma cells. Man-6-P alone increased cell number and neurite outgrowth by approximately 50%; as previously observed, IGF-II increased cell number and neurite outgrowth by approximately 110 and 30%, respectively. However, when cells were grown in the presence of both ligands, cell number increased by 330% and neurite outgrowth by 130%. These results suggest that man-6-P can potentiate the known growth promoting effects of IGF-II on human neuroblastoma cells. Furthermore, they indicate that the IGF-II/man-6-P receptor may serve as a means of integrating distinct growth promoting signals in neuronal cells.