Objective To analyze the clinical efficacy and safety of pemetrexed combined with cisplatin as first-line treatment in the elderly patients with lung adenocarcinoma. Methods A retrospective study was conducted on 76 elderly patients with lung adenocarcinoma admitted in the departments of geriatric respiratory diseases, medical oncology and thoracic surgery of the Shaanxi Provincial People’s Hospital from January 2010 to June 2016. They received the chemotherapy treatment of pemetrexed combined with cisplatin. Another 31 matched patients undergoing gemcitabine plus cisplatin and docetaxel plus cisplatin in the same period served as control. The short- and long-term efficacies were compared between the 2 groups. The data were processed by using SPSS statistics 22.0. Student’s t test, Chi-square test or Fisher exact test were used to compare the data between groups. Kaplan-Meier survival analysis was used to draw the survival curve, and Log Rank test to compare differences between groups. Results There was no case of complete remission (CR) in both group, and no significant difference in the ratio of partial remission (PR) between the 2 groups (P>0.05). For the pemetrexed group, the disease control rate (DCR) was 68.42% (52/76), the ratio of progression disease (PD) was 31.58% (24/76), the time to progression (TTP) was 12.8±2.9 months, and the 3-year survival rate was 31.58% (24/76). While, in the control group, the above indicators were 54.83% (17/31), 45.16% (14/31), 10.6±1.8 months, and 19.35% (6/31), respectively. The pemetrexed group had obviously higher DCR, lower ratio of PD, and better TTP and 3-year survival rate than the control group (P<0.05). Log Rank test showed that the pemetrexed group was superior to the control group in long-term survival rate (χ²=3.97, P<0.05). Conclusion For the elderly advanced lung adenocarcinoma patients carrying wild type epidermal growth factor receptor (EGFR), pemetrexed combined with cisplatin is an acceptable and better regimen, with lower risk for PD and longer survival rate than other chemotherapy regimens.