Background: The radiotherapy (RT)-related toxicities of nasopharyngeal carcinoma (NPC) caused by the standard dose of 70 Gy still remained a critical issue. It is necessary to select optimal candidates for reduced-dose RT. The pretreatment Epstein-Barr virus (EBV) DNA level has been universally applied to select low-risk NPC patients and the response to induction chemotherapy (IC) can be used to screen patients sensitive to RT. In this trial, we assessed whether RT dose of 60Gy was non-inferior to standard dose in low-risk stage III NPC patients with favorable response to IC. Methods: We did a single-arm, single-center, phase II clinical trial in Sun Yat-sen University Cancer Center in China. Patients aged 18-70 with low-risk (EBV DNA level < 4,000 copies/ml) stage III NPC were treated with two cycles IC of TPF regimen (paclitaxel liposome 135 mg/m² on days 1, cisplatin 25 mg/m² on days 1-3, fluorouracil 750 mg/m² as a continuous 120 hours infusion on days 1-5) intravenously given every 3 weeks. Patients with complete/partial response (CR/PR) and undetectable EBV DNA level were assigned 60Gy intensity modulated RT, currently with 100 mg/m² cisplatin intravenously on days 1, 22, and 43. The primary end point was 2-year progression-free survival (PFS). The second end points included: overall survival (OS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS), etc. The trial was registered with ClinicalTrials.gov, number NCT 03668730. Results: Between Nov 19, 2018, and Mar 13, 2020, a total of 216 patients were enrolled in this study, and 1 patient withdrew from the informed consent. 215 patients completed two cycles IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60Gy and 70Gy RT, respectively. For patients treated with 60 Gy RT, 2-year PFS, OS, LRRFS and DMFS were 94% (95% confidence interval [CI], 89 to 99), 100%, 95% (95%CI, 91 to 99) and 97% (95%CI, 93 to 100), respectively, with the median follow-up of 25.8 months (interquartile range 22-28). During RT, the most common toxicity was nausea, with the proportion of 61% (71/116), 5% (6/116) for grade 1-2 and 3. The major grade 3-4 toxicities were leucopenia, neutropenia, mucositis and pain, which were reported in 16 (14%), 16 (14%), 13 (11%) and 15 (13%) patients, respectively. The most common late toxicity was grade 1-2 dry mouth with the incidence of 54% (63/116). No grade 3+ long-term adverse event was observed and no patients died from treatment-related causes. All quality of life items, domains, and symptom scores returned to baseline by 6 months, with the exception of dry mouth and sticky saliva. Conclusions: Our findings show that reduced-dose RT (60Gy) is associated with favorable survival outcomes and limited treatment-related toxicities for low-risk stage III NPC patients sensitive to IC. Clinical trial information: 03668730.