This study demonstrates the existence of sex hormone binding globulin (SHBG) in human cerebrospinal fluid (CSF) by means of a highly sensitive radioligand saturation assay that has been recently described by us for measurement of SHBG in human plasma. The molecular similarity of this 5 alpha-dihydrotestosterone binding protein with plasma-SHBG was substantiated by a number of experiments in which the CSF-protein displayed the same properties as plasma-SHBG with respect to thermolability, affinity, specificity and sedimentation rate. SHBG levels in the CSF of normal women were found to be 0.139 +/- 0.04 nmol/l (mean +/- standard deviation), and in normal men to be 0.083 +/- 0.03 nmol/l respectively. CSF-SHBG in patients with a variety of neurological diseases associated with different degrees of a blood-CSF barrier disturbance, showed a good correlation with commonly determined parameters such as CSF-albumin and CSF-IgG that are known to be of plasma origin. The concept of CSF-SHBG originating from plasma by restricted diffusion is strongly supported by the finding that the CSF/plasma ratio of SHBG is independent of the plasma-SHBG concentration in the entire physiological range. Possible diagnostic and pathophysiological implications of this so far undetected CSF-constituent are discussed with regard to neurological and endocrine abnormalities.