Chronic lymphocytic leukemia is a malignancy of mature B cells that strongly depend on microenvironmental factors and their deprivation has been identified as promising treatment approach for this incurable disease. Cytokine array screening of 247 chronic lymphocytic leukemia serum samples revealed elevated levels of TNF receptor-1 which were associated with poor clinical outcome. We detected a microenvironment-induced expression of TNF receptor-1 in chronic lymphocytic leukemia cells in vitro and aberrantly high expression of this receptor in proliferation centers of patients' lymph nodes. Stimulation of TNF receptor-1 with TNF-α enhanced NFκB activity and viability of chronic lymphocytic leukemia cells which was inhibited by wogonin. Therapeutic effects of wogonin were analyzed in mice after adoptive transfer of Em-TCL1 leukemic cells. Wogonin treatment prevented leukemia development when given early after transplantation. Treatment of full-blown leukemia resulted in loss of TNF receptor-1 on chronic lymphocytic leukemia cells and their mobilization to blood. Targeting TNF receptor-1 signaling is therefore proposed for treatment of chronic lymphocytic leukemia.