The regulation of chromogranin A mRNA was examined in PC12 cells after treatment with nerve growth factor, dexamethasone, or a combination of the two agents. PC12 cells have low levels of chromogranin A mRNA, and this does not change upon treatment with nerve growth factor. Dexamethasone treatment of these cells results in a 4-fold increase in the the amount of chromogranin A mRNA. The dexamethasone-stimulated increase in chromogranin A mRNA is not apparent until at least 16 h after the addition of the drug and is maintained only with continuous culture in the presence of the drug. Dexamethasone and nerve growth factor together increase chromogranin A mRNA to the level seen with dexamethasone alone. Immunohistochemistry shows a similar pattern of protein accumulation within individual cells. Chromogranin B mRNA levels are unaltered by any of the drug treatments described. Treatment with dexamethasone plus NGF seems to be required for full expression of the adrenergic, neuronal phenotype in PC 12 cells. Measurement of chromogranin A mRNA provides more specific delineation of neural differentiation and how it is influenced by hormones and growth factors.