Medial prefrontal cortex (MPFC) damage causes profound behavioral and neuroendocrine alterations. However, many reports have been inconsistent regarding the direction of these effects. We hypothesized that the lesion recovery stage might be a key factor generating discrepancies. To examine changes over time following ibotenic acid lesion in the ventral part of the MPFC, behavioral and endocrine testing was conducted on the second and the fifth week after lesioning. On the second post-lesion week, bilaterally lesioned animals increased social interaction and swimming scores and their corticosterone response to restraint was exaggerated as compared with shams. On the fifth post-lesion week, social interaction and swimming scores were diminished in bilaterally lesioned animals; their basal plasma corticosterone was enhanced, while their corticosterone increase under restraint was blunted relative to shams. These results reveal that the emotional and endocrine responses to stress vary as a function of time following MPFC lesion, which may help to reconcile conflicting reports on effect direction. The role of the MPFC in anxiety, ability to cope with stress and adrenal regulation is also discussed.