To determine the molecular distinction between invasive and non-invasive pituitary adenomas, we evaluated expression of the metastasizing suppressor gene, nm23, in tumors of varying stages. The nm23 gene was recently identified on the basis of reduced expression in highly metastic cancer compared with its expression in low metastatic potential tumors. Twenty-two pituitary tumors (10 nonfunctioning, 9 acromegaly, 2 prolactinomas, and 1 Cushing) were studied. H1 and H2 isoform expression of nm23 was investigated using a ribonuclease protection assay. nm23 H2 messenger ribonucleic acid expression was significantly reduced in invasive tumors and correlated highly (P = 0.0016) with cavernous sinus invasion. In these invasive tumors, sequencing of the nm23 gene did not reveal a mutation. Invasive tumors also demonstrated markedly reduced immunostaining for nm23 H2. These results show the relevance of nm23 gene expression to behavior of these benign tumors. High expression of nm23 H2 is associated with noninvasive pituitary adenomas and may restrain tumor aggression. This molecular defect distinguishing invasive from noninvasive tumors is shown to be a sensitive marker of adenoma invasiveness and may be a predictor for postoperative management plans.