Objective: Lung adenocarcinoma is the most common subtype of non-small cell lung cancer, and also, approximately 25% of lung adenocarcinoma patients have targetable driver mutations. Despite several novel therapeutic advances in the treatment of lung adenocarcinoma with targetable driver mutations, chemotherapy still has an important role to play. In this study, we aimed to evaluate the realworld efficacy of pemetrexed-based chemotherapy in lung adenocarcinoma with the targetable mutation. Material and Methods: The advanced lung adenocarcinoma patients with targetable driver mutations who received pemetrexed-based chemotherapy between 2014 and 2018 were enrolled in this study, retrospectively. The patients were stratified according to mutation type and pemetrexed-line as pre or posttyrosine kinase inhibitor (TKI). The primary outcome of our study was considered as progression-free survival (PFS). Results: A total of 265 patients with the targetable mutation were screened and only 60 were enrolled in the study. In the entire group, the median PFS was 7.81. Median PFS was significantly higher in ALK-ROS1 positive subgroup than EGFR positive subgroup (p=0.001). The median PFS was higher in patients who received pre-TKI treatment in the ALK-ROS1 subgroup (p=0.006). In EGFR positive patients, PFS was similar between pre or post TKI groups (p=0.28). The overall response rate was 55%, 59.1%, and 52.6% in the entire group, ALK-ROS1 positive and EGFR positive subgroup, respectively. Conclusion: We showed that pemetrexed-based therapy is still an important choice for the patients who progress after targeted therapy and also for those who are not suitable for another targeted therapeutic agent.