This study investigated the possible association of the interleukin-1 beta (IL-1beta) C-511T promoter polymorphism and the interleukin-1 receptor antagonist (IL-1Ra) (86bp)(n) variable number of tandem repeats (VNTR) polymorphism with antidepressant response to paroxetine and mirtazapine treatment. The study group consisted of 101 patients suffering from DSM-IV major depression participating in a randomized double-blind controlled clinical trial. Patients homozygous for the IL-1beta-511T allele had a significantly faster and more pronounced response to paroxetine treatment than IL-1beta-511C allele carriers. No association was found for the IL-1beta C-511T polymorphism with mirtazapine treatment response. The IL-1Ra VNTR showed neither an association with paroxetine nor with mirtazapine treatment response. Our results provide further suggestive evidence that time course of response and antidepressant efficacy of paroxetine, but not of mirtazapine, is influenced in a clinically relevant manner by the IL-1beta C-511T gene variant. Our data do not support the hypothesis that the IL-1Ra (86bp)(n) VNTR affects antidepressant treatment response to paroxetine or mirtazapine. An independent replication of our finding is needed. If replicated, the IL-1beta C-511T promoter polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.