ONLY TWO CASES have been reported of a pituitary adenoma that changed phenotype between its initial resection and recurrence. To determine the frequency of such cases among our patients, we examined the clinical course of these tumors and characterized any patterns. We reviewed the charts of 1023 patients with pituitary adenomas who underwent surgery between 1984 and 1992 at the University of California at San Francisco. Of the 65 patients (6.4%) who had operations for or clinical evidence of tumor recurrence, five (7.7%) had tumors that changed phenotype. The female-to-male ratio was 4:1, and age at the onset of symptoms was 33.2 ± 15.3 years (mean ± standard deviation). Changes occurred in hormone production and hormone release after 6.4 ± 3.4 years. At some point, all five tumors were invasive and four were macroadenomas. Two patients had more than one operation for tumor recurrence; three had silent or symptomatic pituitary apoplexy; and three had undergone sellar irradiation before the changes in phenotype occurred. The behavior of these tumors therefore seems to be aggressive. We do not yet know whether phenotypic changes in pituitary adenomas have any treatment implications. Therefore, we advocate the complete immunostaining of primary and recurrent pituitary adenomas so that additional data about their clinical course can be collected.