Objective To compare intra-pleural injection efficacy and safety between Endostar and bevacizumab combined with pemetrexed/cisplatin for the treatment of malignant pleural effusion in patients with epidermal growth factor receptor (EGFR)-/anaplastic lymphoma kinase (ALK)-lung adenocarcinoma. Methods Sixty-four pCVatients with EGFR-/ALK- lung adenocarcinoma with malignant pleural effusion (MPE) were admitted to the authors’ hospital between January 2016 and June 2017. Patients were randomly divided into two groups: Endostar combined with pemetrexed/cisplatin (Endostar group); and bevacizumab plus pemetrexed/cisplatin (Bevacizumab group). They underwent thoracic puncture and catheterization, and MPE was drained as much as possible. Both groups were treated with pemetrexed 500 mg/m2, intravenous drip (d1), cisplatin 37.5 mg/m2 per time, intra-pleural injection (d1, d3). Patients in the Endostar group were treated with Endostar 30 mg per time, intra-pleural injection (d1, 3), and patients in the Bevacizumab group were treated with bevacizumab 5 mg/kg per time, intra-pleural injection (d1). Only one cycle of treatment was applied. MPE was extracted before treatment and on day 7 after treatment. The levels of vascular endothelial growth factor (VEGF) were determined using ELISA. Efficacy and side effects were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. Results The objective response rates in the Endostar and Bevacizumab groups were 50.0% and 56.3%, respectively; there was no statistical difference between the groups (P > 0.05). After one cycle of treatment, the mean VEGF levels in MPE in both groups decreased significantly, and there was no significant difference in the degree of decline between the two groups (P > 0.05). In both groups, pre-treatment VEGF levels for patients achieving complete response were significantly higher than those for patients achieving stable disease + progressive disease (P < 0.05). No specific side effects were recorded. Conclusion Endostar and Bevacizumab demonstrated similar efficacy in controlling MPE in patients with EGFR-/ALK- lung adenocarcinoma through an anti-angiogenesis pathway, with tolerable side effects. The levels of VEGF in MPE could predict the efficacy of intra-pleural injection of anti-angiogenesis drugs.