1. Recently, blunted natural killer cell activity (NKCA) has been found in major depression. The present study investigates the relationships between ex vivo blunted NKCA in major depression, number or percentage of NKC, in vivo indices of systemic immune activation and depressive phenomenology. 2. Toward this end, NKCA, absolute number of leukocytes and number or percentage of lymphocytes, monocytes, neutrophils, activated T lymphocytes (HLA-DR+, CD25+) and NKC (CD3-CD56+) were determined in 13 normal controls and 36 depressed inpatients. 3. NKCA was significantly and positively related to number and percentage of NKC in the peripheral blood. The major depression-related reduction in NKCA was not related to alterations in peripheral NKC. There were significant negative correlations between NKCA and number or percentage of leukocytes, monocytes, neutrophils and HLA-DR+ T cells. Up to 50% of the variance in NKCA could be explained by the regression on the number of monocytes, percentage of HLA-DR+ T and NKC cells, and diagnostic classification. Up to 43% of the variance in NKCA was explained by depressed mood, somatic anxiety and less diurnal variation. 4. The results show that blunted NKCA in major depression is not related to alterations in peripheral NKC, but reflects in part the systemic immune activation in that illness.