Regarding that stress has different effects on biological processes, under stress animals and human beinges show disorders in social behavior and adjustment of HP A axis. Caffeine vegetative phase, root, and in generative phase flower, showed respectively the strongest antimicrobial effect. (C8H10N4O2) is used in some medicines as pain tranquilizer and stimulator of CNS and a wide range effects can HP A axis as well as other effects on many physiological processes in the body. In this research, effects of immobility stress and caffeine have been studied on HP A axis hormonal performance, in male rats. In this study, animals divided, in to control, experimental and sham groups. The animals of the control group were kept in conditions no caffeine and stress, and the animals of the experimental group were injected caffeine with optimum dose for five days and immobility stress for two hours. The animals of the sham group were injected with saline for five days. Plasma hormonal measurement showed a significant increase at ACTH and corticostrone levels in comparison with the control, sham and stress groups and a significant decrease in comparison with the caffeine group, that can be related to the increase of interleukin 6 production and neurotransmitters such as norepinephrine, serotonin, dopamine and acetylcholine in response to stress and caffeine.