Nasopharyngeal carcinoma (NPC) is a malignancy with an unusually variable incidence rate across the world. Radiotherapy is the primary treatment modality for NPC, but radiation resistance remains a serious obstacle to successful treatment in many cases. To identify the genes involved in this resistance and to find molecular markers for predicting NPC response to radiotherapy, we compare the expression profiles of 12 radiation-resistant patient biopsy specimens and 8 radiation-sensitive patient biopsy specimens using DNA microarray, containing 14112 human unigenes. A total of 111 aberrantly expressed genes were identified, of which ZNF608 and CSF1R were up-regulated in the radiation-resistant NPC compared with radiation-sensitive NPC, and the results were confirmed by real-time RT-PCR in 17 independent NPC patient specimens. Biostatistics and bioinformatics analyses were performed to detect the potential pathway underling this resistance, 26 pathways (9 categories) were found probably associated with radiation-resistant NPC, such as cell ion homeostasis, cell proliferation, receptor protein signalling, membrane system, humoral immune response, as well as cytokines and inflammation. We suggest the radiation-resistant capacity of NPC was mostly due to the change of cell Ca²⁺ homeostasis promoting anti-apoptosis, DNA repair and rescuing tumour cells under radiation therapy. Cell proliferation promotion induced by extracellular and intracellular factors may maintain tumour size under radiotherapy leading to recurrence after treatment. Our study reveals that at least 2 ectopically expressed genes play important roles in prognosis of NPC radiotherapy and may serve as potential targets for novel radiation therapeutic strategies in the future.