OBJECTIVE To explore the biological and morphological differences between large Cushing's adenomas and small adenomas, we investigated the clinical, endocrinological, neuroradiological, and histological features of patients with large Cushing's adenomas and compared them with patients with small Cushing's adenomas. METHODS Five of 250 patients with Cushing's disease undergoing trans-sphenoidal operations from 1989 to 1995 had large adenomas with maximum diameters greater than 30 mm. The clinical characteristics of these five patients were compared with the 14 patients with Cushing's disease with small adenomas in our series. RESULTS Oedema, myopathy, and mental disturbance were more frequent and hypertension was less frequent among patients with large adenomas. The high-dose (8 mg) dexamethasone test did not suppress cortisol production in any of the five patients. Invasion into surrounding tissue was demonstrated by magnetic resonance imaging in all five cases. All five large adenomas had scarce or no periodic acid-Schiff-positive granules and were sparsely granulated ultrastructurally. Three tumours contained cells with honeycomb Golgi apparatus which rarely contained immature secretory granules. One Crooke's cell adenoma contained trapped or displaced secretory granules. The other tumour had dilated trans-Golgi network-derived vacuoles that contained reticular or circular electron-dense material. These findings were in striking contrast to those of small Cushing's adenomas, which showed strong PAS positivity, densely-packed granulation, and had prominent Golgi complex harbouring developing secretory granules. CONCLUSIONS We found that the tumour cells in large adenomas produced only small amounts of ACTH, and showed indications of disturbances in the regulated exocytotic pathways. These factors may account for the different clinical characteristics of Cushing's disease with large pituitary adenomas.