Concurrent chemoradiotherapy (CCRT) is superior to radiotherapy alone for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Whether adding induction chemotherapy (IC) further improves the outcome warrants investigation. This open-label multicenter phase III trial was conducted at 11 institutions in Taiwan. Patients with stage IVA or IVB NPC were randomized to receive IC followed by CCRT (I-CCRT) or CCRT alone. Patients in the I-CCRT arm received three cycles of mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL). All patients received 30mg/m2 cisplatin weekly during radiotherapy, which was delivered as 1.8–2.2Gy per fraction with five daily fractions per week, to a total dose of 70Gy or greater to the primary tumor and 66–70Gy to the involved neck. The primary end point was disease-free survival (DFS). In this study, 240 and 239 patients were randomized to CCRT and I-CCRT arm, respectively. The most prominent toxicities of induction were leukopenia (grade 3 and 4: 47% and 12%) and thrombocytopenia (grade 3 and 4: 24% and 3%). During radiotherapy, severe mucositis was the major side-effect in both arms; an increased number of patients in the I-CCRT arm had myelosuppression; hence, discontinuation of weekly cisplatin was more common. After a median follow-up of 72.0months, the I-CCRT arm had significantly higher DFS than that of the CCRT arm 5-year rate 61% versus 50%; hazard ratio=0.739, 95% confidence interval (CI)=0.565–0.965; P=0.0264, after stratified for N3b and LDH, and adjusted for T stage. Induction with MEPFL before CCRT was tolerable and significantly improved the DFS of patients with stage IVA and IVB NPC though overall survival not improved. NCT00201396.