Background: 60-80% of EGFR+ NSCLC could benefit from the treatment of EGFR TKIs. However, as a result of acquired resistance, median progression-free survival (PFS) associated with EGFR-TKIs monotherapy was rarely longer than 11 months. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an important role in the angiogenesis and progression of NSCLC. The combination of EGFR-TKIs and anti-vascular drugs that inhibit the EGFR and VEGF/VEGFR pathways may be a potential therapeutic option for EGFR-mutant NSCLC. The purpose of our study was to evaluate whether gefitinib combined with bevacizumab is associated with an increased PFS benefit compared with gefitinib alone. Methods: This study is a randomized, open-controlled, single-center study. A total of 43 advanced non-squamous NSCLC patients with EGFR L858R mutations were enrolled, including 24 in the experimental group and 19 in the control group. The experimental group received gefitinib combined with bevacizumab (gefitinib 250 mg, QD+bevacizumab 7.5 mg/kg, Q3W), and the control group received gefitinib monotherapy (250 mg, QD). Response to treatment was evaluated after one month of the treatment, followed by once every two months, and adverse events were graded. The primary endpoint was PFS, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety and tolerability evaluation. Samples at baseline (tissue or liquid biopsy), 43 days after treatment (liquid biopsy), and disease progression were subjected to genomic (139-gene NGS panel) profiling. Results: As of December 31, 2020, 22 patients were evaluable (12 for experimental group, 10 for control group). The ORR of the experimental group and the control group were 42% vs 60%, respectively, with no significant difference (experimental group: CR = 0, PR = 5, SD = 7, PD = 0; control group: CR = 0, PR = 6, SD = 4, PD = 0). Main adverse reactions included skin rash (n = 16), diarrhea (n = 24), hypertension (n = 2), proteinuria (n = 1). Other special cases developed fever, nausea and vomiting, elevated platelets, conjunctivitis, back pain, which were manageable. 36 patients with baseline liquid biopsy samples can be evaluated (33 plasma and 3 pleural fluid samples). Of these, EGFR L858R were detectable in 86% (n = 31) of patients. The most common co-mutated gene was TP53 (57%), followed by DNMT3A (49%) and TET2 (17%). Mutation profiles were comparable between the two groups. Conclusions: Compared to gefitinib monotherapy, gefitinib combined with bevacizumab in the treatment of non-squamous NSCLC with EGFR L858R showed similar efficacy and safety profiles.