Sézary syndrome (Sz) is an aggressive cutaneous CD4(+) T-cell lymphoma with tumor cells (Sz cells) localized in the skin, lymph nodes, and peripheral blood. Using western blotting, we demonstrate the expression of phosphorylated (P)-Stat3 in the Sz-derived cell line Seax, and in freshly isolated tumor cells from Sz patients (n=6). In Vitro overnight culture without exogenous cytokines results in decreased expression of P-Stat3 (n=3), indicating that Stat3 is not constitutively activated. Incubation of the Seax cell line with the Jak/Stat3 inhibitor Cucurbitacin I resulted in a time- and concentration-dependent decrease of P-Stat3 and Stat3. In freshly isolated Sz cells (n=3), Cucurbitacin I induced a concentration-dependent decrease in Stat3 expression whereas P-Stat3 was undetectable. Finally, incubation of freshly isolated Sz cells (n=4) with 30 microM Cucurbitacin I for 6 hours induced apoptosis in the large majority (73-91%) of tumor cells. These data strengthen the notion that activation of Stat3 plays an essential part in the malignant transformation of Sz and provide further rationale for the therapeutical targeting of Stat3 in Sz.