Sunitinib (sunitinib malate; SU11248; SUTENT) is a novel multi-targeted receptor tyrosine kinase inhibitor currently approved for the treatment of metastatic renal cell carcinoma. To analyze the possible use of this compound in combination with immunotherapeutic approaches, we investigated the effects of sunitinib on the human peripheral T cells and the induction of primary immune responses in mice. Sunitinib inhibited the proliferation of primary human T cells from normal healthy volunteers as well as from renal cell carcinoma (RCC) and other cancer patients. The inhibition was recoverable after drug withdrawal because sunitinib did not induce T-cell apoptosis even at 0.8 μM. In addition, sunitinib led to accumulation in G0/G1 phase of the cell cycle, inhibition of cytokine production, downregulation of activation markers expression and blockade of Zap-70 signaling in the T cells. Sunitinib significantly reduced the ear swelling induced by picryl chloride in mice. In light of these findings, the effects of sunitinib on the immune system should be emphasized for the therapy of metastatic renal cell carcinoma patients to avoid the impairment of T lymphocytes.