Objective: To investigate the efficacy of a treatment regimen (gefitinib + chemotherapy) in patients with epidermal growth factor receptor (EGFR)(+) advanced non-small cell lung cancer (NSCLC), and investigate the effect of the treatment on tumor markers. Methods: A total of 90 patients with EGFR(+) advanced NSCLC treated in Nantong Tumor Hospital from January 2018 to December 2019 were selected. Among them, 45 patients receiving gefitinib single-drug targeted intervention were included in a control group, and 45 patients receiving gefitinib, metrexed disodium, and cisplatin intervention were included in a treatment group. After treatment, the clinical efficacy, changes of serum tumor markers, survival and incidence of adverse drug reaction (ADR) were compared between the 2 groups. Results: The objective remission rate (ORR) and disease control rate (DCR) of the treatment group were significantly higher than those of the control group (73.3% vs 51.1%, 88.9% vs 71.1%, P<0.05). The incidence of ADR was slightly higher in the treatment group than that in the control group (51.1% vs 40.0%, P=0.29). After treatment, the contents of carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and cytokeratin 19 fragment (CYFRA21-1) in the 2 groups were significantly lower than that before treatment (P<0.05). In addition, the average CEA, CA199 and CYFRA21-1 contents in the treatment group were significantly lower than those in the control group (P<0.05). Overall survival (OS) and progression-free survival (PFS) in the treatment group were significantly better than those in the control group [OS: (22.10±0.53) months vs (17.96±0.67) months, PFS: (9.61±0.39) months vs (6.55±0.46) months, P<0.05]. Patients with EGFR19 deletion had significantly better OS and PFS than those with 21 L858R mutation [OS: (21.63±0.69) months vs (18.70±0.71) months, PFS: (9.14±0.46) months vs (7.22±0.45) months, P<0.05]. After 4 courses of treatment, the content of CD3⁺ and CD4⁺ was significantly increased, the ratio of CD4⁺ to CD8⁺ was significantly increased, and the content of CD8⁺ was significantly decreased (P<0.05). In addition, compared with the control group, the content of CD3⁺, CD4⁺, CD4⁺/CD8⁺ was significantly higher in the treatment group, while the content of CD8⁺ was lower (P<0.05). Conclusion: Gefitinib combined with chemotherapy has a definite effect on patients with EGFR(+) advanced NSCLC, which can effectively inhibit the development of the disease, improve the immune function of patients, reduce the level of tumor markers in serum, and improve survival without increasing serious ADR. Therefore, it is worthy of clinical promotion and application.