Objective: To study the clinical effect of ENDOSTAR combined with platinum-based chemotherapy on advanced non-small cell lung cancer with pleural effusion in acute episode. Methods: Selected 100 patients with advanced non-small cell lung cancer with pleural effusion acute episodes from March 2014 to January 2014 in our hospital, according to the random lottery, divided the patients into the observation group and control group, control group patients given pure of platinum-based chemotherapy, observation group were given ENDOSTAR combined with platinum-based chemotherapy treatment, and after the treatment, observed the clinical curative effect in both groups. Results: After treatment, the overall remission rate of observation group was 88%, the total quality of life period was 82%, which were both significantly higher than those in control group with response rate (56%), quality of life (44%), the differences were statistically significant (P<0.05); after treatment, the hydrothorax VEGF, HIF-1α level in the observation group were respectively (334.7±81.4) pg/mL and (42.7±3.9) ng/L, which were significantly lower than those in the control group with hydrothorax VEGF level (451.7±93.2) pg/mL, HIF-1α level (48.9±3.2) ng/L; and tumor markers level of observation group was obviously lower than that of the control group, the difference were statistically significant (P<0.05); 69 patients had adverse reactions during treatment in the observation group, while 68 had in control group, the difference had no significant difference (P>0.05). Conclusion: ENDOSTAR combined platinum-based chemotherapy on advanced non-small cell lung cancer patients with pleural effusion in acute episode has significant clinical effect, effectively reduces pleural effusion VEGF, HIF-1α level, and will not increase the occurrence of adverse reactions.