Ten adrenocortical carcinomas including two tumors with clinically detectable corticosteroid production, were immunohistochemically analyzed for their intermediate filament proteins, and for neuroendocrine markers. Keratins were present in 6 of 10, vimentin in all 10, and the 68 kilodalton kD neurofilament subunit protein in 6/10 tumors. Keratins numbers 8 and 18 were most prevalent, whereas only traces of keratins 19 and 7 were found. Eight tumors were positive for synaptophysin at least focally, and 3 showed extensive positivity in more than 30% of tumor cells. The tumors showed approximately similar levels of neuron-specific enolase (NSE) expression as judged by immunohistochemistry. Chromogranin was not detected, and there was no immunoreactivity for 3 neuropeptides (calcitonin, gastrin, somatostatin). In normal adrenal cortex, neuron-specific enolase, synaptophysin and neurofilaments were restricted to the nerves seen between the cortical cells. Electron microscopy revealed clusters of dense-core granules in 4 of 5 tumors, consistent with neuroendocrine granules. These results indicate that adrenocortical carcinomas may show signs of neuroendocrine differentiation and share some features with the adrenal medullary tumors.