〔Abstract〕 Objective To investigate the therapeutic effect of pemetrexed combined with gefitinib on patients with advanced lung adenocarcinoma. Methods A total of 92 patients with advanced lung adenocarcinoma treated in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2020 were randomly divided into a control group and an observation group, with 46 cases in each group. The control group was treated with gefitinib monotherapy, and the observation group was treated with pemetrexed combined with gefitinib. The short-term efficacy, adverse reactions, tumor marker levels, survival and quality of life of patients in the two groups were compared. Results The objective remission rate and disease control rate in the observation group were 65.22% and 86.96%, respectively, which were significantly higher than 45.65% and 73.91% in the control group, the differences were statistically significant (P < 0.05). After treatment, the levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) in the observation group were lower than those in the control group, and the differences were statistically significant (P < 0.05). The progression-free survival time and overall survival time in the observation group were longer than those in the control group, and the differences were statistically significant (P < 0.05). After treatment, the scores of physical status, emotional status, functional status, social/family status, functional assessment of cancer therapy (FACT-L) scale in the observation group were higher than those of the control group, the differences were statistically significant (P < 0.05). ConclusionPemetrexed combined with gefitinib has a good therapeutic effect in patients with advanced lung adenocarcinoma, which can enhance tumor inhibition, reduce the level of tumor markers, prolong the survival time, improve the quality of life, and do not increase the incidence of adverse reactions.