beta-Endorphin immunoactivity was measured in the plasma and cerebrospinal fluid (CSF) of 13 patients with metastatic cancer 1 day before and 5 days after complete transsphenoidal hypophysectomy. Preoperatively, mean beta-endorphin-like immunoactivity in plasma was 18.2 +/- 3.5 pg/ml (SEM) and in CSF 32.3 +/- 6.3 pg/ml. No correlation was noted between the concentration of beta-endorphin in plasma and CSF. Postoperatively, plasma beta-endorphin was undetectable (less than 7 pg/ml) in 12 patients and was low (9.6 pg/ml) in 1 patient. In CSF, however, beta-endorphin was detectable in 10 of the 13 patients postoperatively, with a mean of 14.0 +/- 2.2 pg/ml. Chromatography on Sephadex G-50 of CSF extracts pooled from 3 patients after hypophysectomy showed that the majority of beta-endorphin immunoactivity eluted in the same position as synthetic human beta-endorphin. We conclude that beta-endorphin becomes undetectable in plasma after hypophysectomy in patients receiving exogenous glucocorticoid replacement but remains detectable in significant amounts in CSF. It appears, therefore, that a considerable portion of the beta-endorphin in CSF is of nonpituitary origin, most likely resulting from synthesis and secretion of this peptide by brain directly into the CSF.