Background: Patients with N2-3 nasopharyngeal carcinoma have a high risk of failures, despite the current practice of concurrent adjuvant cisplatin-5-fluorouracil (PF) regime. Adjuvant PF regimen may not be adequate for tumor control of high risk patients, emphasizing the need for more effective regimen of adjuvant chemotherapy in N2-3 nasopharyngeal carcinoma. Methods: We conducted this multicentre, open-label, phase 3, randomised, controlled trial in four centers in China. Patients aged 18–65 years with stage T1–4N2–3 nasopharyngeal carcinoma were randomly assigned (1:1) to receive concurrent cisplatin (100mg/m2 intravenously) on days 1, 22, and 43 of radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1) (GP) once every 3 weeks or 5-fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 4 weeks for three cycles. Randomisation was by a computer-generated random number code with a block size of six, stratified by treatment centre and nodal stage (N2 or N3). The primary endpoint was 3-year progression-free survival in the intention-to-treat population. This study is registered in ClinicalTrials.gov, NCT03321539. Results: From October 30, 2017 to July 9, 2020, 240 were randomly assigned to PF group (n = 120) or GP group (n = 120). After a median follow-up of 40 months (IQR: 32-48), the 3-year progression-free survival was 83.9% (95% CI 75.9–89.4) in GP group and 71.5% (62.5–78.7) in PF group (stratified HR 0.54; 95% CI, 0.32 to 0.93; p = 0.023). Significantly lower cumulative incidence of locoregional relapse (2.6% vs. 12.5%; HR 0.33; 95% CI, 0.12 to 0.90; Fine-Gray p = 0.030) and distant metastasis (10.4% vs. 20.1%; HR 0.50; 95% CI, 0.26 to 0.98; Fine-Gray p = 0.042) were also observed in GP group than PF group. However, there was no effect on early 3-year overall survival (90.7% vs. 94.0%; HR 1.12; 95% CI, 0.50 to 2.55; log-rank p = 0.779). Overall incidence of treatment-related adverse events was not significant different between the two treatment groups in the concurrent phase. In the adjuvant phase, significant higher incidence of grade 3-4 leucopenia (42 [41.2%] vs. 19 [16.8%], p < 0.001), neutropenia (33 [32.0%] vs. 10 [8.9%], p = 0.001) and thrombocytopenia (9 [8.7%] vs. 2 [1.8%], p = 0.044) was observed in GP group than PF group, whereas the frequency of diarrhea (6 [5.3%] vs. 0 [0%], p = 0.030) and mucositis (21 [18.6%] vs. 7 [6.8%], p = 0.010) was higher in PF group than in GP group. Conclusions: Concurrent adjuvant GP regimen significantly improved progression-free survival in patients with N2-3 nasopharyngeal carcinoma with acceptable toxicity. Long term follow-up is needed to confirm the ultimate therapeutic ratio. Clinical trial information: NCT03321539.