Objective To investigate the effect of the expression of miRNA-106b-5p on the prognosis of non-small cell lung cancer (NSCLC) patients who received targeted therapy. Methods A total of 273 NSCLC patients who underwent targeted therapy from January 2012 to October 2013 in Dalian University Affiliated Xinhua Hospital were included. Fasting venous blood samples of all the hospitalized patients within 24 hours were collected, real time fluorescence quantitative polymerase chain reaction was used to measure the expression of miRNA-106b-5p, and their survival status were followed up. Kaplan-Meier method and log-rank test were used for survival analysis. Cox regression model was used to make multiple-factor analysis. Results There were 112 males and 161 females among 273 patients. The age was (61 ±12) years old. There were 40 patients having family history of cancer, 70 patients having smoking history. According to TNM stage, 77 patients were classified into stageⅠ, 39 patients were classified into stage Ⅱ, 107 patients were classified into stage Ⅲ and 50 patients were classified into stage Ⅳ. The relative expression level of miRNA-106b-5p was 1.72±0.67. Until October 2018, 27 out of 273 NSCLC patients lost follow-up. Of 246 follow-up patients, 185 patients (75.2％) died. The results of single factor survival analysis showed that family history of cancer (HR= 1.16, 95％ CI 1.07-1.31), smoking history (HR= 2.17, 95％ CI 2.08-3.26), advanced differentiation degree (HR=1.63, 95％CI 1.43-2.19), higher TNM stage (HR= 2.09, 95％CI 1.75-2.17), and high expression of miRNA-106b-5p (HR=2.37, 95％CI 1.63-3.63) were associated with the poor prognosis of NSCLC patients treated with targeted therapy. Multivariable Cox regression analysis showed that family history of cancer (HR= 1.15, 95％CI 1.09-1.27), smoking history (HR= 2.11, 95％CI 2.08-2.82), higher differentiation degree (HR= 1.42, 95％CI 1.31-1.89), higher TNM stage (HR= 2.07, 95％ CI 1.83-1.95), higher miRNA-106b-5p expression (HR=2.21, 95％CI 1.81-3.25) were the independent risk factors affecting the prognosis of NSCLC patients treated with targeted therapy. Conclusion The high expression of miRNA-106b-5p is associated with the increased risk of death among NSCLC patients treated with targeted therapy.