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Objective To investigate the factors that impacts of therapeutic effect in advanced non-small cell lung cancer (NSCLC) patients with mild tumor enlargement and the rational therapeutic strategy for them. Methods The clinicopathological features and prognostic data of advanced NSCLC patients whose sum of tumor longest diameters with 0 to 20% increase were retrospectively explored, and the Cox proportional hazards model was used to analyze the independent prognostic factors in patients. Results The median progression-free survival (PFS) of 54 patients with the original regimen was 87 days, significantly less than 168 days of the median PFS of 49 patients with replacing regimen (P<0.001). The median PFS of other chemotherapeutic regiems (154 days) and the targeted therapy (287 days) were longer than the origional therapy (P<0.05 for all). The left 7 patients received radiotherapy. Receiver operating characteristic (ROC) curve indicated a significant difference in the PFS when the maximal cut-off value of tumor enlargement ratio was 7%. Univariate analysis of patients with targeted therapy after disease progression showed that gender, pathological type, clinical stage, lung metastasis and tumor enlargement ratio were the prognostic factors (all of P<0.05). Multivariate analysis showed that the tumor enlargement ratio was an independent prognostic factor (P=0.001). Single factor analysis showed that the chemotherapeutic regimens before and after disease progression were prognostic factors of patients received chemotherapy after disease progression (P<0.05). Cox multivariate analysis showed that the chemotherapeutic regimen after disease progression was an independent prognostic factor of patients (P=0.004). In the patients whose tumor enlargement ratio was 0 to 7%, Univariate analysis showed that chemotherapeutic regimen before tumor enlargement was a prognostic factor (P=0.030), while Cox multivariate analysis showed that it was not an independent prognostic factor (P=0.560). In the patients whose tumor enlargement ratio was 7.1% to 20%, single factor analysis showed that pathological type, bone metastasis and chemotherapeutic regimen after disease progression were prognostic factors (all of P<0.05), and Cox multivariate analysis showed that all of them were independent prognostic factors of these patients (all of P<0.05). Conclusions To the advanced NSCLC patients whose tumor enlargement ratio is 0 to 20%, the PFS of patients receive replacing regimen is longer than that of patients receive original regimen. There is a significant difference in the PFS when the maximal cut-off value of tumor enlargement ratio is 7%. To patients undergo second-line chemotherapy before disease progression and the tumor enlargement ratio is 7.1% to 20%, the PFS of patients receive replacing regimen is significantly extended. Dual drug replacing regimen is especially benefit to the adenocarcinoma patients without bone metastasis. [ABSTRACT FROM AUTHOR]