The effects of previous chronic immobilization stress on the physiological responses of male rats to a novel chronic stressor (shock) were studied. Previous chronic exposure to immobilization reduced adrenocorticotropin (ACTH) and lactate responses to acute immobilization stress without altering the response to a novel acute stressor (tail shock). When subjected to chronic tail shock, body weight inhibition caused by chronic shock was greater in the rats not previously exposed to chronic immobilization, which suggests that there is a cross-adaptation between different stressors. However, adrenocorticotropin adaptation to chronic shock was impaired by previous chronic immobilization. These data indicate that the existence of cross-adaptation to stressors might depend on the variable measured, the central nervous system pathway controlling the pituitary-adrenal axis being, apparently, resistant to cross-adaptation. This lack of cross-adaptation at certain levels can assure the maintenance of an adequate response to unknown environmental stimuli.