Neuroendocrine secretory protein-55 (NESP-55) is a recently described member of the chromogranin family and appears to be a marker of the constitutive secretory pathway in certain neural, neuroendocrine, and endocrine cell types. It has been shown to be selectively expressed in tumors differentiating towards the adrenal chromaffin and pancreatic islet cell phenotypes. The highest levels of NESP-55 expression, at least in animals, appear to be in the adrenal medulla and the pituitary gland. However, very little is known about the status of NESP-55 expression in pituitary adenomas. We therefore studied the immunohistochemical profile of NESP-55 expression in a series of 30 well-characterized pituitary adenomas (five each of FSH/LH and ACTH, four GH, three TSH, seven prolactin, and six null cells). All tumors were positive for one or more generic marker(s) (chromogranin A, synaptophysin, neuron-specific enolase) of neuroendocrine differentiation. All pituitary adenomas selected for study were stained for NESP-55 with appropriate positive and negative controls. NESP-55 immunoreactivity, seen as brown finely granular cytoplasmic staining of the tumor cells with prominent perinuclear accentuation, was graded as focal (<10% tumor cells staining), moderate (10–50% tumor cells staining), and diffuse (>50% tumor cell staining). Four of seven prolactinomas were positive for NESP-55 (one focal, two moderate, and one diffuse). Two of four GH adenomas were also positive (one focal and one diffuse) while only 1/5 FSH tumors showed a moderately intense immunoreactivity. All other pituitary adenomas were completely negative for NESP-55. Our results indicate that, in human pituitary adenomas, NESP-55 has a more restricted pattern of expression than that of chromogranins A and B. Since immunohistochemical expression of NESP-55 is largely confined to prolactinomas and GH adenomas, it raises the possibility that NESP-55 may somehow be involved in the secretory pathways of these specific cell types.