The biologic behavior of invasive pituitary adenomas is poorly understood and appears to be intermediate between intrasellar adenomas and pituitary carcinoma. Utilizing immunohistochemistry on tissue sections, we examined 10 invasive pituitary adenomas involving the sphenoid sinus with a panel of cellular and molecular markers and compared the results with 10 noninvasive pituitary adenomas and five normal pituitary glands. The panel included Ki-67 and PCNA (proliferation cell nuclear antigen), cell proliferation indicators; interleukin 6 (IL-6), a multifunctional cytokine; heat shock protein 27 (HSP 27), a stress response protein; and p53, a tumor suppressor gene product. We found strong expression of IL-6 in normal pituitary glands, 20% of noninvasive and 50% of invasive adenomas. HSP 27 was absent in normal glands and present in 10% of noninvasive and 50% of invasive adenomas. The Ki-67 and PCNA proliferation index was above normal but was essentially the same in the two groups. p53 was not detected in any specimens. We propose that both IL-6 and HSP 27 may be markers of biologic aggression in pituitary adenomas.