The known interaction between the immune system and the hypothalamic–pituitary–adrenal axis led us to explore the interrelation between magnetic resonance imaging findings and the hypothalamic–pituitary–adrenal axis activity in 53 multiple sclerosis patients. The cortisol release induced by the dexamethasone-corticotropin-releasing hormone test was negatively associated with the presence and number of gadolinium-enhancing lesions and positively associated with ventricular size. This finding suggests a protective effect of the hypothalamic– pituitary–adrenal drive on acute lesional inflammation in multiple sclerosis, probably by limiting immune overshoot. In contrast, the nature of the correlation between hypothalamic–pituitary–adrenal hyperdrive and brain atrophy remains to be determined.