Background: Weight loss during radiotherapy has been known as a negative prognostic factor for nasopharyngeal carcinoma (NPC) patients, but the factors related to weight loss during radiotherapy were not fully understood. Methods: A total of 322 newly diagnosed NPC patients receiving intensity modulated radiotherapy (IMRT) in Sun Yat-sen University Cancer Center between June 2002 and August 2006 were enrolled. Kaplan-Meier methods and log-rank test were applied for survival analysis; a multiple regression was used to identify the factors related to weight loss during radiotherapy. Results: The mean and median values of weight loss (%) during radiotherapy were 6.85% and 6.70%. NPC patients with critical weight loss (>5.4%) have poorer overall survival (OS) and distant metastasis-free survival (DMFS) than the patients without critical weight loss (p = 0.002 and 0.021, respectively). Pre-radiotherapy weight, acute mucosal toxicity, acute pharynx and esophagus toxicity, and acute upper gastrointestinal toxicity were related to the weight loss during radiotherapy independently (p = 0.01, p < 0.001, p < 0.001, and p = 0.009, respectively). Conclusions: Acute radiation toxicities had significant and independent impact on weight loss during radiotherapy. The vicious circle of acute radiation toxicities and weight loss had bad effect on prognosis of NPC patients.