Adrenal adenomas frequently arise from cortical islets in the medulla, and these islets seem to present a greater risk for pathological growth than cortical cells within the adrenal cortex. Chromogranin A (CgA), a glycoprotein co-stored in secreting granules and co-released with resident hormones of chromaffin cells, behaves as a prohormone, generating several biologically active peptides capable of influencing growth, morphogenesis and progression of endocrine tumors. The aim of our study was to investigate whether chromaffin cells may be involved in the development and growth of adrenocortical adenomas. We enrolled 19 patients (12 females and 7 males, mean+/-SD age 54.9+/-11.2 yr, age range 34-75 yr) with incidental, non-functioning, benign adrenocortical adenomas, and measured circulating levels of CgA, catecholamines and creatinine before and 2 months after surgery. Plasma CgA was evaluated by immunoradiometric assay. Testing for CgA immunoreactivity in the removed tissues was performed by immunohistochemical analysis. Mean plasma CgA did not significantly change following surgery (before 73.7+/-15.2 ng/ml; after 68.9+/-14.8 ng/ml). Individual CgA values indicated that 4 patients had plasma CgA levels above our cut-off of normality. After mass removal, CgA further increased in 2 cases, decreased in 1 and normalized in 1. No variation in CgA levels was found in the other patients. No correlation was observed between CgA and the variables measured, except between CgA and plasma creatinine (r=0.472, p<0.05). Histopathological evaluation revealed adrenocortical adenomas in all cases and immunohistochemical analysis detected no CgA immunoreactivity in any specimen. Our results show that in human adrenocortical adenomas CgA is not expressed and that removal of the mass does not modify plasma CgA levels. For these reasons the endocrine involvement of local CgA in adrenocortical tumorigenesis is unlikely.