Background: DAB₃₈₉ IL-2 is a novel fusion toxin that retargets the cytotoxic A-chain of diphtheria toxin to interleukin-2 (IL-2) receptor–expressing tumors. Objective: The purpose of this phase I trial was to study the toxicity, maximum tolerated dose, and clinical efficacy of DAB₃₈₉ IL-2 in IL-2 receptor expressing lymphoproliferative malignancies, including cutaneous T-cell lymphoma. Methods: DAB₃₈₉ IL-2 was administered intravenously daily for 5 days every 3 weeks. Dose escalation occurred between patient groups. Patients were monitored for laboratory and clinical toxicity, kinetics, immune response, and clinical efficacy. Results: Thirty-five patients with cutaneous T-cell lymphoma (including 30 patients with mycosis fungoides) were treated. Previously, conventional therapy had not worked for 34 of the patients. Thirteen patients (37%) achieved an objective response, including a complete response in five patients (14%). Complete response was achieved in patients with extensive erythroderma and tumor stage mycosis fungoides. Adverse events consisted of reversible fever/chills, hypotension, nausea/vomiting, and elevation of hepatic transaminase. Doses of less than 31 μg/kg per day were well tolerated. Clinical responses were observed at all dose levels. Conclusion: DAB₃₈₉ IL-2 is well tolerated at doses of less than 31 μg/kg per day, and it induced clinical responses in previously treated mycosis fungoides, providing evidence for the antitumor activity of this molecule. (J Am Acad Dermatol 1998;39:63-73.)