Mogamulizumab, a humanized defucosylated anti C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell leukemia/lymphoma. This phase 2 study evaluated efficacy and safety of mogamulizumab in adult T-cell leukemia/lymphoma patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the United States, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n = 47) or investigator choice of chemotherapy (n = 24). The primary endpoint, overall response rate confirmed on a subsequent assessment at 8 weeks by blinded independent review, was 11% (95% CI, 4% to 23%) and 0% (95% CI, 0% to 14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95% CI, 0.41-1.21) and, after post hoc adjustment for performance status imbalance, 0.57 (95% CI, 0.337-0.983). The most frequent treatment-related adverse events grade ≥3 with mogamulizumab were infusion-related reaction and thrombocytopenia (each 9%). Relapsed/refractory adult T-cell leukemia/lymphoma is an aggressive, poor prognosis disease with a high unmet need. Investigator choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% confirmed overall response rate, with a tolerable safety profile. This trial was registered at www.clinicaltrials.gov as NCT01626664.