Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations administered in 16 patients with chronic back pain and 18 healthy control subjects. Results showed that patients with chronic back pain have higher levels of cortisol than control subjects. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus, a region involved in anticipatory anxiety and associative learning. Importantly, path modelling-a statistical approach used to examine the empirical validity of propositions grounded on previous literature-revealed that the cortisol levels and phasic pain responses in the parahippocampal gyrus mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the sustained endocrine stress response observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states.