Over the last 15 years, an increasing body of evidence has suggested a causal relationship between depression and the immunological activation and hypersecretion of pro-inflammatory cytokines, such as interleukin-1, interleukin-6 and tumor necrosis factor-alpha (TNF-alpha). However, little is known about the probable relationship of serum TNF-alpha with major depressive disorder (MDD). To assess whether serum TNF-alpha levels could be associated with the clinical course of MDD. TNF-alpha and C-reactive protein (CRP) serum concentrations, erythrocyte sedimentation rate, and leukocyte count were measured in 26 MDD patients and in 17 controls. The measurements were repeated following 6 weeks of antidepressant treatment with selective serotonin re-uptake inhibitors. Psychopathological improvement and the severity of depression were evaluated with the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI). On admission, serum TNF-alpha and leukocyte count were significantly higher in MDD patients compared to controls ( P<0.001 and P=0.005, respectively). With the antidepressant treatment, both HAMD and BDI scores decreased significantly (P<0.001 for both). Comparison of pre- and post-treatment measurements revealed that TNF-alpha, CRP, and leukocyte count decreased to levels comparable with those of the control subjects ( P<0.001, P=0.01, and P=0.01, respectively). The results emphasized that some immunological parameters, such as CRP, leukocyte count and TNF-alpha, are significantly involved in the clinical course and treatment response in MDD. TNF-alpha in particular could be considered as a potential state marker in MDD.