Background: No standard of care for elderly patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established yet. We assessed the efficacy of an anti-CCR4 antibody, mogamulizumab (Moga) combined with biweekly cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisone (PSL) (Moga-CHOP-14) for untreated elderly patients with aggressive ATL. Methods: In this phase 2 trial conducted at 21 centers in Japan, untreated CCR4-positive aggressive ATL patients aged 66 years or older and 56-65 years who were not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT) received six cycles of Moga-CHOP-14, followed by two cycles of Moga monotherapy. The primary endpoint was 1-year progression-free survival (PFS), defined as the time from enrollment to the progression/relapse of ATL or death due to any cause, whichever occurred first. Secondary endpoints were complete response rate (CR), overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and the incidence of adverse events. The necessary number of patients calculated by setting the threshold 1-year PFS at 16% and the expected 1-year PFS at 31% using the exact method based on binomial distribution under the conditions of one-sided level of significance of 5% (α = 0.05) and power of 70% was 43. Results: A total of 50 patients were enrolled from October 2015, until September 2020. Among the 48 evaluable patients, the median age was 74 years (interquartile range [IQR], 70-78). ATL subtypes included 31, 9, and 8 patients for the acute, lymphoma, and unfavorable chronic type, respectively. ATL-PI included 9, 31, and 8 patients for high, intermediate, and low risk, respectively. With a median follow-up of 1.6 years (IQR, 0.7-2.4), 1-year PFS was 36.2% (90% confidence interval (CI), 24.9-47.6), and a median PFS was 0.7 years (95% CI, 0.5-1.0). CR and ORR were noted in 64.6% (95%CI, 49.5-77.8), and 91.7% (95% CI, 80.0-97.7), respectively. One-year OS was 66.0% (95% CI, 50.6-77.6) and median OS was 1.6 years (95%CI, 1.1-2.8). One-year EFS was 29.9% (95% CI, 17.6-43.2) and median EFS was 0.5 years (95%CI, 0.4-0.7). The most frequent adverse events grades 3/4, which occurred in > 10% of patients were lymphocytopenia (97.9%), leukopenia (93.8%), neutropenia (89.6%), febrile neutropenia (64.8%), anemia (58.3%), thrombocytopenia (45.8%), infection (27.1%), skin rash (20.8%), and hyperglycemia (20.8%). Relative dose intensity (RDI) was calculated for each drug: the mean RDI for Moga was 82.1%, for CPA 71.7%, for DXR 72.7%, for VCR 72.0%, and for PSL 77.3%. Conclusions: This study demonstrated that Moga-CHOP-14 significantly improved PFS in elderly patients with aggressive CCR4-positive ATL who were ineligible for allo-HSCT. Moga-CHOP-14 is now considered for the preferred first-line treatment in those patients. Clinical trial information: jRCTs041180130.