PURPOSE: UKALL 2011 randomly assigned children and young adults (younger than 25 years) with ALL or lymphoblastic lymphoma. The aims were to reduce induction toxicity (randomization 1 [R1]), CNS relapse risk (randomization 2 [R2]-interim maintenance [R2IM]), and maintenance morbidity (R2pulses). METHODS: R1 compared induction dexamethasone (dex) for 28 days (6 mg/m; standard) with 14 days (10 mg/m; short). R2 was a factorial randomization resulting in four arms: high-dose methotrexate (HDM) with pulses, HDM without pulses, standard interim maintenance (SIM) with pulses (standard of care), and SIM without pulses. The primary end points were reduction in steroid-related toxicity (R1), CNS relapse rate (CNSR, R2IM), and bone marrow relapse rate (BMR, R2pulses; ALL only, noninferiority margin 5%). Event-free survival (EFS) was an additional primary end point for both randomizations. RESULTS: Of 2,750 eligible patients registered between April 2012 and December 2018, 1,902 were randomly assigned to R1 and 1,570 to R2. Median follow-up is 99 (R1) and 87 months (R2). There were no differences in steroid-related toxicity between short and standard dex (23.8% 25.5%; = .41) and CNSR between SIM and HDM (0.98 [95% CI, 0.65 to 1.49]; = .94; 5-year rates: SIM 5.3% and HDM 5.5%). EFS was no different between R1 and R2IM arms. BMR in the no pulses arm was noninferior (+1.7% increase at 5 years [95% CI, -1.5 to 4.1]; hazard ratio [HR], 1.19 [95% CI, 0.87 to 1.62]; = .27). Although the EFS in the no pulses arm was inferior (1.34 [95% CI, 1.05 to 1.73]; = .021), this was not significant for relapse (HR, 1.24 [95% CI, 0.96 to 1.62]; = .10). CONCLUSION: Shorter duration of induction dex does not reduce steroid-related toxicity and HDM does not improve CNSR within a UKALL treatment backbone. Omission of pulses is noninferior for BMR.