Background: Primary mediastinal B-cell lymphoma (PMBCL) has a good prognosis if remission is rapidly achieved with dose‐intensive immunochemotherapy. In these patients mediastinal radiotherapy (RT) may consolidate responses; however, it increases the risk of second malignancies and coronary or valvular heart disease. The IELSG37 trial was planned with a non-inferiority design to test whether RT can be omitted in patients who achieve a complete metabolic response (CMR) after immunochemotherapy. Methods: Patients with newly diagnosed PMBCL were eligible. Initial rituximab and anthracycline-based therapy was chosen according to local practice. CMR was defined, upon central review of positron emission computed tomography (PET/CT) scans, as Deauville score 1 to 3, according to the Lugano classification. Responding patients were randomized to observation (OBS) or consolidation RT (30 Gy). Randomization was stratified on gender, chemotherapy regimen, country, and PET/CT score. The primary endpoint was progression-free survival (PFS) after randomization. The sample size (540 patients to enrol, and 376 to randomize) was calculated assuming a 30-month PFS probability of 0.85 in both arms, with alpha at 0.05, 80% power and a hazard ratio (HR) of 1.77 as non-inferiority margin. Results: At a median follow-up of 30 months, the number of observed events was considerably lower than expected, hence, the Independent Data Monitoring Committee (IDMC) of the trial recommended to complete the planned total accrual without increasing the study size or duration. The primary endpoint analysis was performed, according to the IDMC recommendation, with ≥80% of patients having a minimum follow-up of 30 months. 545 patients (209 men, 336 women) were enrolled. Induction immunochemotherapy was completed and response assessed in 530 patients, 268 of them (50.6%) achieved a CMR and were randomly allocated to OBS (n = 132) or RT (n = 136). The PFS at 30 months was 98.5% (95%CI, 94.3 – 99.6) in the RT arm and 96.2% (95%CI, 91.1-98.4) in the OBS arm (P = 0.278). The estimated relative effect of radiotherapy vs observation in terms of hazard ratio (HR) was 0.47 (0.12-1.89) without adjustments and 0.79 (0.19-3.31) after stratification for the variables used for randomization. At 30 months the absolute risk reduction from RT was 2.3% (-1.5 to 6.2) unadjusted, and 0.8% (-3.0 to 8.3) with stratified HR. The number needed to treat is high (43 patients, unadjusted, and 126 after stratification). The 5-year overall survival was 99% in both arms. Longer follow-up is needed to examine late toxicity. Conclusions: This study is the largest prospective study of PMBCL ever conducted and although the event rate did not reach the assumed level, its evidence supports the omission of RT in patients achieving a CMR after immunochemotherapy.