The immune system and its relation to psychiatric disorders has attracted many investigators, but there is still great controversy about the extent of immunological changes associated with different psychiatric disorders. Bipolar disorder is the least studied among the three major psychiatric disorders: schizophrenia, major depression and bipolar disorder. The current study was conducted on 20 patients with mania in comparison to 20 healthy controls, to evaluate changes in percentage of lymphocytes, active T-lymphocytes and natural killer (NK) cells. We found a significant decrease in the percentage of lymphocytes in mania patients as compared to controls. Assessment of Active T. lymphocyte (HLADR+) and NK cell (CD56+) by flowcytometry using a battery of paired (FITC and PE) monoclonal antibodies, revealed significant decrease in NK cells (P < 0.001), while no significant difference was found between patients and controls as regards percentage of active T lymphocytes. It is concluded that the immune response is altered in manic patients. However, further studies on large number of cases using various immunological parameters related to CMI are needed to confirm these findings.