Stress response is an important neuroendocrine function. Overt or prolonged stress hormone secretion can lead to various disease states. The hippocampus plays an important role in the negative feedback onto the major player in the stress response, the hypothalamo-pituitary-adrenal axis. The transcription factor c-Fos is activated in the hippocampus following a number of stressors, including restraint stress. To determine whether c-fos modulates stress response, we previously generated mutant mice carrying a hippocampal mutation of the c-fos gene. In the current study, we found that female mutant mice display lower anxiety-like behavior than female wild-type mice in the elevated plus maze, whereas male mice are apparently normal. While both male and female mutant mice exhibit normal diurnal glucocorticoid (CORT) production and normal responses to acute restraint stress, female mutant mice habituated faster than female wild-type mice in response to chronic restraint stress. These findings suggest that hippocampal c-fos plays a role in gender-dependent response to stress. © 2006 Elsevier Ireland Ltd. All rights reserved.