Background: Nasopharyngeal carcinoma (NPC) is one of the most highly radiosensitive malignancies; however, some locally advanced NPC patients experienced local recurrence even though they received aggressive treatment regimens. Defining the tumor volume precisely is important to escalate the total dose required for the primary tumor. In this study, we aimed to investigate the feasibility and efficacy of dose escalation guided by DW-MRI in patients with locally advanced NPC. Patients and Methods: A total of 230 patients with locally advanced NPC treated with intensive modulated radiotherapy (IMRT) at Sichuan Cancer Hospital between January 2010 and January 2015 were enrolled in this retrospective study. All the patients were treated with all-course of simultaneous integrated boost-IMRT. DW-MRI-guided dose escalation with 2.2–2.5 Gy/F, qd for 1–3daysor1.2–1.5 Gy/F, bid for 1–3 days were prescribed to 123 patients. Survival and complication of the patients were evaluated, and multivariate analysis was performed. Results: The median follow-up of patients in the DW-MRI-guided dose-escalation group and the conventional group was 48 months (range 8–88 months) and 52 months (range 6–90 months), respectively. The 5-year overall survival rate, distant metastasis-free survival rate, progression-free survival, and local recurrence-free survival (LRFS) of patients in the dose-escalation group and the conventional group were 88% vs 82.5% (p = 0.244), 86.1% vs 83.3% (p = 0.741), 82.2% vs 76.6% (p = 0.286), and 89.1% vs 80.1% (p = 0.029), respectively. Multivariate analysis showed that dose escalation was independent prognostic factor for LRFS (HR 0.386, 95% CI 0.163–0.909, p = 0.03). Conclusion: DW-MRI-guided dose escalation is a feasible strategy to improve local control of patients with locally advanced NPC. The treatment-related complications are tolerable. © 2020 Huang et al.