Summary Background Obsessive-compulsive disorder (OCD) has been associated with an altered activity of the immune system. This study was carried out to investigate whether treatment with paroxetine and venlafaxine modifies the immune function in OCD and whether this modification is related to treatment outcome. Methods Ex vivo production of TNF-α, IL-4, IL-6, IL-10, and IFN-γ in whole blood cultures, and NK-cell activity and peripheral blood NK-cell-, monocytes-, T-cell-, and B-cell- percentages were measured in 42 outpatients with OCD who participated in a 12-week, double-blind SRI trial. Results Paroxetine and venlafaxine treatment did not affect immune parameters and clinical response was not directly related to altered activity of the immune system. Responders, defined as having a ≥25% decrease on the Y-BOCS, differed from non-responders with regard to the change of TNF-α values. Conclusions The present results suggest that paroxetine and venlafaxine do not affect immune parameters and that clinical response is not related to altered activity of the immune system in OCD. Nonetheless, our data yielded interesting preliminary results that warrant further discussion and investigation.