Objective: To observe the efficacy and safety of apatinib plus epidermal grouth factor receptor tyrosine kinase inhibitor (EGFR-TKI) as a first-line treatment for advanced non-squamous non-small cell lung cancer (nsNSCLC) with activating epidermal growth factor receptor (EGFR) mutations. Methods: From August 2016 to August 2018, it was planned to enroll 20 patients with stage IIIb or IV nsNSCLC with sensitive EGFR mutations. All patients were treated with apatinib in combination with EGFR-TKI drugs until disease progression, intolerant toxicity or patient withdrawal. RECIST version 1.1 and NCI-CTCAE version 4.0 were used to evaluate the efficacy and safety, and the survival was analyzed according to the follow-up data. Results: In the middle of the enrollment process, the incidence of grade 3 and above adverse reactions was as high as 88.3% (5/6), and the study was suspended in August 2017. There were 4 males and 2 females, with the median age of 69 (range 55-83), and 1 case of stage IIIb and5 cases of stage IV. Four patients received apatinib combined with gefitinib, and two received apatinib with icotinib. Among 6 patients, 2 patients received the continuous doublet regime until the disease progressed with overall response rate (ORR) of 100%, median progression-free survival (PFS) of 17.6 mo and median overall survival (OS) of 32.8 mo. For the other 4 cases with grade 3 adverse reactions, apatinib was stopped and treated with EGFR-TKI continuously, and ORR was 50% with the median PFS of 15.0 mo and median OS of 25.6 mo. The most common treatment-related grade 3 to 4 adverse events were hand-foot syndrome in 1 case (16.7%), stomatitis in 1 case (16.7%), anorexia in 2 case (33.3%), liver dysfunction in 1 case (16.7%), renal dysfunction in 1 case (16.7%) and hypertension in 1 case (16.7%). Conclusion: Apatinib plus EGFR-TKI as the first-line treatment for advanced nsNSCLC with EGFR mutations had suspected benefits in PFS and OS, but adverse events limited its use. The combination significantly increased the incidence of grade 3 and 4 adverse reactions that mainly included hand-foot syndrome, stomatitis, anorexia and liver dysfunction. However, age might be a beneficial factor, which needs to be confirmed by further studies.