Abnormalities in several neurotransmitters, including neuropeptides, have been found in postmortem studies of Alzheimer's disease (AD). Recently, corticotropin-releasing factor (CRF) was found to be diminished in cerebral cortex. In this study spinal fluid CRF-immunoreactivity (CRF-I) was determined in 16 patients with mild to moderate AD and 9 age-matched controls. Mean CRF-I levels were significantly lower in Alzheimer patients compared with controls. Furthermore, a tendency for a CRF-I increment with successive spinal fluid aliquots in control subjects was absent in Alzheimer patients. CRF-I levels failed to correlate with measures of disease severity or various tests of cognitive function. These results suggest that involvement of CRF containing neurons may play a secondary rather than a primary role in the pathophysiology of AD.