Background: To assess the impact of comorbidity on the initiation of chemotherapy and its ultimate treatment outcomes in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: Data on 1316 patients with NPC treated between February 2003 and January 2007 was retrospectively reviewed. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) system. The association of various factors with chemotherapy was evaluated. And treatment outcomes of chemoradiotherapy regimes in patients with comorbidity were compared. Results: Comorbidity was present in 42.2% of patients; mild, moderate and severe comorbidity were observed in 33.6%, 8.1% and 0.5% of patients, respectively. Comorbidity (as indicated by ACE-27 score) was a negative prognostic factor for overall survival (OS) (hazard ratio HR=1.577; P < 0.001) and disease-free survival (DFS) (HR=1.509; P < 0.001). In stage III-IV NPC, T classification, N classification, age, sex and hemoglobin before treatment were significant predictors of the initiation of chemotherapy (P < 0.05). Additionally, in stage III-IV patients with comorbidity (ACE > 0), 5-year OS for the concomitant chemoradiotherapy group (CCRT) was 74.5% vs. 56.9% in the radiotherapy (RT) only group (P = 0.008), the 5-year DFS rate was 64.0% in the CCRT group vs. 49.4% for RT only (P = 0.015). Conclusions: Comorbidity should be assessed during treatment strategy decision-making to improve survival in NPC. Concomitant chemoradiotherapy is feasible and effective in patients with comorbidity in locoregionally advanced stages.