The BCR-ABL kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). However, long-term imatinib treatment induces immunosuppression, which is mainly due to T cell dysfunction. Imatinib can reduce TCR-triggered T cell activation by inhibiting the phosphorylation of tyrosine kinases such as Lck, ZAP70, LAT, and PLC γ 1 early in the TCR signaling pathway. The purpose of this study was to investigate whether the superantigen SEA, a potent T cell stimulator, can block the immunosuppressive effects of imatinib on T cells. Our data show that the exposure of primary human T cells and Jurkat cells to SEA for 24 h leads to the upregulation of the Lck and ZAP70 proteins in a dose-dependent manner. T cells treated with SEA prior to TCR binding had increased the tyrosine phosphorylation of Lck, ZAP70, and PLC γ 1. Pretreatment with SEA prevents the inhibitory effects of imatinib on TCR signaling, which leads to T cell proliferation and IL-2 production. It is conceivable that SEA antagonizes the imatinib-mediated inhibition of T cell activation and proliferation through the TCR signaling pathway.