Aims: The standard treatment for patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy (CRT). However, CRT is associated with late adverse events (AEs). This multi-institutional, randomized controlled trial (JCOG1912) aimed to confirm the non-inferiority of reduced prophylactic radiation (RT) with 40 Gy (Arm B: 2-step40) to standard prophylactic RT with 56 Gy (Arm A: simultaneous integrated boost technique, SIB56) in pts with LA-SCCHN. Methodology: The trial enrolled LA-SCCHN pts with Stage III-IVB (excluding N3a) of the oropharynx (p16(-)), hypopharynx, and larynx, aged 20 years or more, and ECOG-PS 0-1. All pts received a definitive dose of 70 Gy with IMRT to the primary and neck disease with concurrent 3-weekly cisplatin (100 mg/m2). Primary endpoint was time to treatment failure 1 (TTF1), defined as the time from enrollment to the earliest occurrence of death, disease progression, residual tumor after CRT, or discontinuation of protocol treatment. A total sample size of 400 pts was planned to achieve 75% power, with an accrual period of 5 years, follow-up period of 3 years, and non-inferiority margin of 1.32 for the hazard ratio (HR). Results: At the interim analysis in March 2025, the Data and Safety Monitoring Committee recommended early termination due to futility. A total of 281 patients were included in the updated analysis (Arm A, 140 pts; Arm B, 141 pts). With a median follow-up of 1.1 year, 2-year TTF1 was 70.6% in Arm A and 58.2% in Arm B (HR, 1.43; 95% CI, 0.93-2.21 [>1.32]). In 157 pts with hypopharyngeal cancer (Arm A, 79 pts; Arm B, 78 pts), 2-year TTF1 was 68.8% in Arm A and 56.1% in Arm B (HR, 1.55; 95% CI, 0.88-2.75). For late AEs, Arm B showed a slightly favorable trend for hearing loss and hypothyroidism. Conclusions: JCOG1912 failed to prove non-inferiority of 2-step40 to SIB56. Therefore, the standard prophylactic dose with SIB56 is recommended for LA-SCCHN pts who receive definitive CRT.