Several neurobiological mechanisms contribute to the development of ischemic-reperfusion damage of the central nervous system that may be modulated by hypothermia. Nowadays hypothermia is a therapeutic tool for the treatment of stroke and perinatal asphyxia. Hypothermia does not only affect the central nervous system, but also has systemic effects. It influences the muscular and cardiovascular system, the systematic metabolism, induces electrolyte changes, and decreases inflammation. This review summarizes the effects of therapeutic hypothermia on the immune system. Experiments on cell lines and in animals along with human experience indicate that short term (2-4 hours) hypothermia increases the levels of anti-inflammatory cytokines and decreases that of proinflammatory cytokines. Long term (>24 hours) hypothermia, however, increases proinflammatory cytokine levels. Furthermore, hypothermia inhibits lymphocyte proliferation and decreases HLA-DR expression associated with cell activation. These results suggest that therapeutic hypothermia has a systemic immunomodulatory effect. Further research is required to determine the contribution of immunomodulation to the defense of the central nervous system.