Targeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major challenges in the therapeutic management of CTCL patients creating an urgent need for new, effective therapies. Pathologic constitutive NF-κB activity leads to apoptosis resistance in CTCL cells and thus represents a promising therapeutic target in CTCL. In a preclinical study we showed the potential of dimethyl fumarate (DMF) to block NF-κB and specifically kill CTCL cells (Nicolay et al.: Blood 2016). To translate these findings into a clinical setting, we performed a multicentric phase II study evaluating oral DMF therapy in 25 patients with CTCL stage Ib-IV over 24 weeks (EudraCT number 2014-000924-11/NCT number NCT02546440). Endpoints were safety and efficacy. We evaluated skin involvement (mSWAT), pruritus, quality of life and blood involvement if applicable as well as translational data. In the skin, 7/23 patients (30.4%) showed a response with >50% reduction in mSWAT. Patients with high tumor burden in skin and blood responded best to DMF therapy. Although not generally significant, DMF also improved pruritus in several patients. Response in the blood was mixed, but we confirmed the NF-κB inhibiting mechanism of DMF in the blood. The overall tolerability of the DMF therapy was very favorable with mostly mild side effects. In conclusion, our study presents DMF as an effective and excellently tolerable therapeutic option in CTCL to be further evaluated in a phase III study or real-life patient care as well as in combination therapies.