Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): The Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. Patients and Methods COG AALL0434 included a 2 3 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. Results AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival (P = .005) and overall survival (P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. Conclusion AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.