BACKGROUND Pituitary surgery is the standard treatment for Cushing's disease but is complicated by a recurrence rate that ranges from 5.9 to 27%. Whereas some recurrences may be due to technical or anatomical factors resulting in subtotal resection of adenoma, clinical relapse after total tumor resection is a well-documented occurrence. The factors leading to such recurrences are unknown. METHODS With the hypothesis that the pathology of the nontumoral adenohypophysis is important in predicting relapse, we undertook a study to determine if the absence of Crooke's change (CC), thought to be an indicator of nontumoral corticotroph inhibition, was associated with unexpected clinical recurrence. Twenty-one patients with Cushing's disease, with gross total resection of intrasellar corticotroph microadenoma, were reviewed independently by 2 neuropathologists for the presence of CC in adjacent adenohypophysis. All tumors were stained with H&E, PAS/orange-G and immunohistochemistry for ACTH. Clinical relapse was determined by chart reviews and defined as serum ACTH > 15 pg/ml, clinically Cushingoid, and/or radiographic evidence of recurrent tumor. RESULTS Seven of 21 patients recurred; 3 did not have CC in their initial resection specimen. All 3 of these patients had unexpected recurrences at 6 to 48 months post-op. Two patients with CC recurred at one year follow-up, 1 after 4 years and 1 after 5 years. All specimens from patients with long-term cure (follow-up from 9-72 months) contained CC. In this study, the absence of CC in peritumoral adenohypophysis was associated with unexpected recurrence of Cushing's disease (p = 0.0214). CONCLUSIONS We conclude that absence of CC in peritumoral adenohypophysis may be of some assistance in predicting recurrence of Cushing's disease after adequate resection of intrasellar microadenoma.