We investigated the relationship between hypothalamic-pituitary-adrenal (HPA) activity, as measured by 24-hour mean urinary free cortisol (MUFC), and cerebrospinal fluid (CSF) opioid activity in patients with major affective disorder and normal volunteers. Among depressed patients, but not normal volunteers, mean 24-hour urinary cortisol values were significantly correlated with CSF opioid activity measured by radioreceptor assay, but were not significantly correlated with beta-endorphin immunoreactivity measured by radioimmunoassay. MUFC, as expected, was significantly higher in depressed patients than in normal volunteers. Mean values of CSF opioid activity and beta-endorphin immunoreactivity did not differ significantly in the two groups. The positive opioid-MUFC correlation found in the depressed group appeared to depend on patients who were cortisol hypersecretors. These data, using relatively crude measures of cortisol and opioid activity, are suggestive of a relationship between these two systems, particularly under "activated" conditions such as those observed in depression.