Background Induction chemotherapy regimens of docetaxel and cisplatin plus fluorouracil (TPF) are currently clinically used for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) but have well-known side effects, such as myelosuppression and diarrhea. A docetaxel plus cisplatin (TP) regimen was developed to decrease the toxic effects induced by fluorouracil. In this trial, we assessed whether the TP induction chemotherapy regimen was noninferior to the TPF regimen. Methods We performed an open-label, noninferiority, phase 3, multicentre, randomised, controlled trial at six centres in China. Eligible patients with NPC (stage III-IVA (excluding T3-4N0), Karnofsky's Performance Scoring >= 70) were randomly assigned (1:1) to receive either TP (docetaxel (75 mg per square meter, d1, intravenous infusion) and cisplatin (75 mg per square meter of body-surface area, d1, intravenous infusion)) or TPF (docetaxel (60 mg per square meter, d1, intravenous infusion) plus cisplatin (60 mg per square meter, d1, intravenous infusion) and 5-fluo-rouracil (600 mg per square meter, d1-d5, intravenous 120-hour infusion)) administered every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy. The primary endpoint was failure-free survival at 2 years. Secondary endpoints included overall survival, safety, and treatment compliance. The trial was stopped early because of strong evidence for noninferiority (margin was-10%) of TP in failure-free survival. Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations and we included the patients who started treatment in each group for the safety analysis. The study was registered with chictr.org.cn, ChiCTR1800016337. Findings Between June 1, 2018 and October 31, 2021, we randomly assigned 361 patients to the TP (n =181) or TPF (n = 180) induction chemotherapy group. The 2-year failure-free survival was 91.3% (95% CI 86.2-96.4) in the TP group and 82.4% (84.8-88.9) in the TPF group (P = 0.029). Patients in the TPF group had a higher frequency of grade 1 or 2 neutropenia (53 (30.0%) vs. 28 (15.7%); P = 0.0010), grade 1 or 2 diarrhea (20 (11.3%) vs. 9 (5.1%); P = 0.032), and grade 3 or 4 neutropenia (43 (24.3%) vs. 25 (14.0%); P = 0.014) in the induction chemotherapy period. There was no treatment-related death. Interpretation The preliminary results revealed that TP induction chemotherapy regimen was found to be clearly non-inferior compared to the TPF regimen in failure-free survival, with a lower frequency of neutropenia, anaemia eClinicalMedicine 2022;53: Published https://doi.org/10.1016/j. eclinm.2022.101625 and diarrhoea. The more convenient and beneficial survival regimen of the TP regimen should be recommended in patients with LA-NPC. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.