Glycosaminoglycans (GAGS), localized on the surfaces of cells and in the basement membrane, modulate the growth and differentiation of many cell types. Recent studies have shown that heparin, a GAG found in mast cells, potentiates the ability of acidic fibroblast growth factor (aFGF) to induce neurite outgrowth in pheochromocytoma (PC12) cells. We examined the effect of a variety of GAGs on aFGF, basic fibroblast growth factor (bFGF), and nerve growth factor (NGF)induced neurite outgrowth in PC12 cells. The effects observed were dependent upon the specific GAG, the concentration of the GAG, and the growth factor. Heparin potentiated aFGF-induced neurite outgrowth in a concentrationdependent fashion; potentiation increased with increasing heparin concentrations of 0.01-100 p,g/mI. At concentrations greater than 100 pg/ml, heparin potentiation decreased. The maximally active concentration of heparin (1 00 p,g/ml) increased the potency of aFGF 102-fold. Increasing concentrations of heparan sulfate, dermatan sulfate, and chondroitin sulfate correlated with increasing aFGF potentiation. The maximally active concentrations of heparan sulfate (1 00p,g/ml), dermatan sulfate (10 mg/ml), and chondroitin sulfate (1 mg/ml) increased the activity of aFGF 1 1 -, 1 lo-, and 11-fold, respectively. Hyaluronic acid did not affect the neurite outgrowth-promoting activity of aFGF. Heparin also altered the activity of bFGF; increasing concentrations of heparin (0.01-1 p,g/ml)