Although several recent studies deal with various molecular aspects of apoptosis, or programmed cell death, very little information is available on the ultrastructural changes associated with apoptosis in the adenohypophysis and its role in the regulation of pituitary adenoma growth and progression. This paper describes the distinct ultrastructural sequences that develop during the various phases of the apoptotic process. The study is based on the ultrastructural investigation of more than 8,000 surgically removed pituitary biopsies, which were examined by histology and immunocytochemistry for diagnostic purposes. No apoptosis was found in normal adenohypophysis and it is also a rare event in pituitary adenomas. When present, adenomatous adenohypophysial cells exhibit common and characteristic apoptotic changes. The ultrastructural alterations of membraneous organelles associated with apoptosis are similar to those previously reported in other tissues. It is noteworthy that apoptosis is clearly distinguishable from the ubiquitous dark cells denoting the common way of cell death. The findings suggest that apoptosis in pituitary adenomas is not a random event. Practically every specimen containing multiple apoptotic cells represents corticotroph adenoma. Occasional examples occur in lactotroph or gonadotroph adenomas. Although electron microscopic specimens are admittedly small, the large number of investigated cases gives credence to the observations.