Nasopharyngeal carcinoma (NPC) is one of the predominant cancers found in Southeastern China and Taiwan. Chemotherapy is one of the major treatment modalities, and the cisplatin-based regimen is the front-line treatment. However, NPC patients failing to cisplatin treatment will have a compromised survival. To explore the resistance spectrum and mechanisms of cisplatin resistance in NPC, two cisplatin-resistant sublines (cis6 and cis15) derived from the parental NPC cell line HONE-1 were obtained. Compared with HONE-1 cells, cis6 and cis15 cells showed upto 18-fold resistance to cisplatin in each, and also possessed a cross-resistance to oxaliplatin and arsenic trioxide. The level of platinum-DNA-adduct and γH2AX were significantly decreased in cis6 and cis15 cells. To unravel the behind details, the systems of DNA repair and cisplatin detoxification were examined and found to be more active in both resistant cells. In terms of the DNA repair proteins, the levels of p-DNA-PK and XRCC1 were increased; in terms of cellular localization of cisplatin, the level of copper transporter ATP7A was upregulated; in terms of Nrf2/antioxidant/detoxifizing enzyme, the resistant cells had a higher Nrf2 activity and an increased intracellular level of GSH, GR, NQO1, AKR1C1 and AKR1C2. Moreover, as compared with HONE-1 cells, our results showed that the resistant cells spared the cisplatin-induced cell death via the suppression of pro-apoptotic proteins and the enhancement of anti-apoptotic proteins. Since the members of ErbB family could be overexpressed in NPC and the ErbB/Akt/FoxO axis could involve in the actions of apoptosis, DNA damage repair and detoxification of reactive oxygen species, the ErB/Akt/FoxO were investigated. Indeed, the phosphorylations of Akt, FoxO1, and FoxO3 were upregulated in cis6 and cis15 cells. Thus, the resistance to cisplatin in cis6 and cis15 cells was partially explained by the Akt/FoxO pathway. Surprisingly, EGFR was downregulated in the resistant cells, whereas ErbB2 was upregulated. The elevations of the negative regulators of EGFR, including c-Cbl, GCF and LRIG1, were observed in cis6 and cis15 cells, indicating that the negative regulation of EGFR could be at the levels of transcription and protein degradation. Since LRIG1 could be upregulated and negatively feedback to control the level of ErbB after the ErbB was activated, it was plausible that the overexpression of ErbB2 upregulated the expression of LRIG1 and subsequently, caused the downregulation of EGFR. Nevertheless, the hypothesis which both overexpression of ErbB2 and LRIG1 contributes to the resistance to cisplatin in our cell model awaits experimental verification. Taken together, our results suggested that the mechanism responsible for cisplatin resistance in NPC, at least in part, through Akt/FoxO pathway.