Background: Cisplatin-based chemoradiotherapy(CRT) has been widely applied as a first-line regimen in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, cisplatin can induce severe side effects .Our previous phase II trial revealed that lobaplatin combined with 5-fluorouracil (5-FU) followed by concurrent chemoradiotherapy (CCRT) showed encouraging anti-tumor effects with tolerable toxicities for LA-NPC. Here, we assess the efficacy and toxicities of a regimen of lobaplatin versus cisplatin plus 5-FU as induction chemotherapy (ICT) followed by concomitant lobaplatin versus cisplatin with intensity-modulated radiotherapy (IMRT). Methods: Stage III-IVB NPC patients were randomly assigned to receive lobaplatin or cisplatin plus 5-FU as ICT followed by CCRT. In the lobaplatin arm, patients received lobaplatin at a dose of 30 mg/m² on days 1 and 22 combined with a continuous 120-h intravenous injection of 5-FU at a dose of 4 g/m² followed by lobaplatin at a dose of 30 mg/m² on days 43 and 64 concomitant with IMRT. Lobaplatin was replaced by cisplatin (100mg/m²) in the cisplatin arm. The primary end-point was progression-free survival (PFS). Results: Of the 494 eligible patients, 250 were assigned to lobaplatin arm and 244 to cisplatin arm. No difference was observed in overall tumor response between two arms (98.6% vs. 97.7%, P= 0.459). After a median follow-up of 42.6 months, no statistically significant differences in 3-year PFS rate was observed between two arms (PFS: 78.9% vs. 82.0%, P= 0.985). During ICT, more patients suffered grade 3-4 leucopenia, neutropenia, nausea and vomiting in cisplatin arm (all P< 0.001). During CCRT, grade 3-4 anemia, nausea and vomiting were more common in cisplatin arm (all P< 0.001). Conclusions: The regimen of ICT with lobaplatin plus 5-FU followed by concomitant lobaplatin and IMRT achieved similar survival outcomes with less acute toxicity compared to cisplatin-based CRT in LA-NPC. Long-term follow up is required to determine whether lobaplatin-based systemic chemotherapy should be the first line of therapy for LA-NPC. Clinical trial information: ChiCTR-TRC-13003285.