Objective  To jointly detect the differences of mRNA expressions of ERCC1, RRM1, TYMS, and TUBB3 of non-small cell lung cancer (NSCLC) patients with wild type epidermal growth factor receptor (EGFR) and explore the effects of expressions of 4 genes on the efficacy and prognosis of chemotherapy. Methods  Patients with wild type EGFR were screened by xTAG liquid phase chip method from samples of 353 NSCLC patients. The mRNA expression levels of 4 genes were detected by real-time PCR. Patients with wild type EGFR were divided into the high expression group (expressions of 4 genes were high) and low expression group (expressions of 4 genes were low). The median progression free survival and median overall survival of two groups were compared after chemotherapy. Results  A total of 227 NSCLC patients with wild type EGFR were screened. The differences of mRNA expression levels of 4 genes of patients were not statistically significant (P>0.05) except differences between smoking and non-smoking patients. There were 27 patients in the high expression group and 53 patients in the low expression group. The differences of the objective remission rate (ORR) (14.8% vs 41.5%, P<0.05), disease control rate (DCR) (40.7% vs 81.1%, P<0.05), median progression free survival (3.3 m vs 4.9 m, P=0.001), and median overall survival (7.1 m vs 8.1 m, P=0.048) of two groups were statistically significant. Cox multivariate analysis showed that the high expression of 4 genes was independent risk factor of prognosis for NSCLC patients with wild type EGFR after chemotherapy (HR=1.92;95%CI: 1.10-3.42). Conclusion  High mRNA expressions of ERCC1, TYMS, TUBB3, and RRM1 in cancer tissue of NSCLC patients with wild type EGFR indicate that they are resistant to chemotherapeutic drugs. Joint detection of expressions of 4 genes is helpful for choosing chemotherapy plans.