Background: Patients with MYC rearrangement positive large B-cell lymphoma (MYC LBCL) have a dismal prognosis; retrospective studies report complete remission rates <50% and 2-year overall survival (OS) rates of approximately 35% following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Intensive chemotherapy regimens yield higher remission rates, but do not improve OS. Prospective trials are lacking. Lenalidomide, an oral immunomodulatory drug which downregulates MYC and its target genes, can be combined with R-CHOP. Methods: We conducted a prospective phase II trial evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC LBCL patients recruited from a nationwide screening program for MYC rearrangements. The primary endpoint was complete metabolic remission (CMR) at end-of-treatment (EOT) on centrally reviewed positron emission tomography (PET)-computer tomography (CT) scan. Secondary endpoints were disease-free survival (DFS), event-free survival (EFS), OS, and the predictive value of interim PET-CT (iPET-CT) scan for EOT result. Findings: Eighty-two patients ≥ 18 years, stage II-IV, were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 15·9 months, 1-year estimates for OS and DFS were 85% (95% CI 76-91%) and 77% (95% CI 65-85%), respectively. Positive and negative predictive value of iPET-CT were 60% and 79% respectively. The R2CHOP regimen turned out to be safe. Interpretation: In this first prospective phase II trial for newly diagnosed MYC LBCL patients we found that administering R2CHOP is safe, yields superior CMR and survival rates compared to R-CHOP, is at least as effective as intensive in-hospital chemotherapy regimens and can be administered on an outpatient basis. Hence, our findings offer new prospects for MYC LBCL patients and could change current clinical practice. Funding Statement: Celgene funded the research, provided lenalidomide free of charge, approved the original protocol and all amendments as written, but had no role in either the design of the study, the collection, analysis, and interpretation of the data, nor the preparation of the manuscript. The Dutch Cancer Society provided funding for the screening program and the clinical trial. The corresponding author had full access to all the study data and had final responsibility for the decision to submit for publication. Declaration of Interests: MC received institutional research funding from Gilead, Genmab, and BMS. MN received institutional research funding from Takeda and Nordic vector. RM received institutional research funding from Gilead, Takeda and reports consultancy for Takeda, Janssen Cilag, Abbvie, BMS, Celgene, MSD, Roche, and Sandoz. OV reports consultancy for Sanofi. PL received institutional research funding from Servier, Takeda and reports consultancy for Takeda, BMS, Celgene, Sandoz, Servier, Roche, Genmab. AD reports consultancy for Takeda. JZ received institutional research funding from Roche and Gilead and reports consultancy for Roche, Janssen, BMS, Takeda, Gilead, Mundipharma, and Karyopharm. MK received institutional research funding from Celgene and Roche and reports consultancy for Celgene and Roche. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the medical ethics committee of the Amsterdam University Medical Centres (VU University, Amsterdam). All the participants provided written informed consent. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. An independent data and safety monitoring board conducted review during the planned interim analysis.