Chemoresistance and cancer recurrence are a major obstacle in therapeutic treatment. Our previous studies have showed that smoking results in poor survival in HPV positive head and neck cancer, but the mechanism remains unclear. In this study we demonstrated that compared with primary tumors and parental cancer cells, there was significantly downregulated expression of a long noncoding RNA (PTENP1) in recurrent HPV positive head neck tumor and smoking induced cancer cells which results in c-MYC activation and drug resistance. Moreover, there are significantly increased expression of HPV16 E2, E6, E7 oncogenes in all paired recurrent tumors. The increasing expression of HPV16 E5, E6 or E7 oncogenes suppress the expression of PTENP1 in head and neck squamous cell carcinomas (HNSCC). Depletion of c-MYC also decreased the expression of the HPV16 oncogenes E7 in HPV positive HNSCC cells. We further found that smoking inhibits the expression of PTENP1 by deactivation of PKC family. Phorbol 12-myristate 13-acetate (PMA), a PKC activator re-sensitized smoking induced cancer cells to cisplatin via PTENP1/c-MYC pathway. This is the first study demonstrating a prognostic value of lncRNA PTENP1in tumor drug resistance and recurrence. This novel mechanism for smoking induced drug resistance via PTENP1-MYC axis may have important implication in the development of PKC activator for overcoming smoking induced drug chemoresistance and recurrence.