Clinical observations and animal studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis plays a role in the susceptibility to and the recovery from multiple sclerosis (MS). Since the HPA-axis is under the control of corticotropin-releasing hormone (CRH) neurons of the hypothalamus, we determined 2 parameters for activation of the CRH neurons in the hypothalamic paraventricular nucleus (PVN) in MS patients. Since the HPA-axis is more activated in MS, we expected an increased activity of CRH neurons. We also expected to see an age-related increase in CRH activity, because of the possible role of the HPA-axis in the age-related decrease in susceptibility to MS. The number of CRH cell profiles and the proportion of CRH neurons co-expressing vasopressin were used as parameters for activity. CRH cell population became more activated both in control and MS patients, from 40 years of age onwards, when the prevalence of MS starts to decrease in the population. The CRH neurons showed a significantly higher level of activation in MS patients than in controls, as appeared from the 3-fold increase in CRH cell number and the 4.5-fold increase in cells co-expressing CRH and vasopressin (AVP).