There is now some evidence that major depression is accompanied by an immune response with an increased production of pro-inflammatory cytokines, such as interleukin 1(IL-1), IL-6 and interferon gamma (IFN-gamma). The aims of the present study were to examine serum IL-6, IL-1 receptor antagonist (IL-1Ra), IL-6R, Clara cell protein (CC16) and the soluble CD8 (sCD8) molecule in chronic, treatment resistant depression (TRD) both before and after subchronic treatment with antidepressants. Serum IL-6 and IL-1Ra were significantly higher in subjects with major depression and TRD than in normal controls. Subchronic treatment with antidepressants had no significant effects on serum IL-6, IL-1Ra, CC16 or sCD8, but reduced serum sIL-6R levels significantly. There were significant and positive correlations between serum IL-6, on the one hand, and sIL-6R, IL-1Ra, sCD8, number of peripheral blood leukocytes, neutrophils, CD2(+)T and CD19(+)B cells (all positive) and serum zinc (negative), on the other. These results suggest that: (1) major depression and TRD are accompanied by an activation of the monocytic arm of cell-mediated immunity; (2) the latter may be related to the immune an acute phase response in major depression; and (3) the above disorders may persist despite successful antidepressive treatment.