The impact of anti-TNF therapy on systemic immune responses in patients has not been clearly defined. Here, we examined Th1/Th2/Th17 cytokine expression, activation and proliferation of peripheral T cells from patients with psoriasis and inflammatory bowel disease before and during anti-TNF therapy. In parallel, we calculated the correlation with the clinical response and we monitored cytokine expression in biopsies from inflamed tissues. We evidenced a dual role of TNF-blockade. In peripheral blood, it increased the expression of cytokines such as IL-17, IL-10, and IFN-γ, and enhanced the expression of activation markers and the proliferative response of CD4 T cells to TCR stimulation. By contrast, in biopsies from target tissues, TNF-blockade diminished the expression of Th17/Th1 cytokine and early inflammatory genes. Importantly, the enhanced T cell responses to TCR-stimulation did not impair the clinical response to the therapy and, in responder patients, occurred with the concomitant down-regulation of inflammatory genes in the target tissues.