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To investigate the effect of combined epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway inhibitors on progression-free survival (PFS) and overall survival (OS) in patients with non–small-cell lung cancer (NSCLC).We included 15 randomized clinical trials that had compared the combination of EGFR tyrosine kinase inhibitors and anti-VEGF/VEGFR therapy with different control groups. Pooled estimates of treatment efficacy were calculated, and subgroup analyses were conducted according to treatment line and EGFR status.Ten of 15 trials involving 3317 NSCLC patients were included. For all settings, the combined regimen demonstrated no PFS (hazard ratio [HR], 0.82; P = .10) or OS (HR, 0.97; P = .54) benefit compared with the control groups. In the first-line setting, combined therapy showed similar PFS (HR, 1.01; P = .99) but poor OS (HR, 1.36; P = .03) compared with the control groups. In the second-line or subsequent settings, combined therapy resulted in significantly longer PFS (HR, 0.75; P < .01) but similar OS (HR, 0.93; P = .16) compared with the control groups. A subgroup analysis stratified by EGFR status suggested that combined treatment substantially improved PFS (HR, 0.57; P = .04) and OS (HR, 0.45; P < .01) in patients with EGFR mutations rather than EGFR wild type.EGFR-tyrosine kinase inhibitors plus anti-VEGF/VEGFR therapy significantly prolonged PFS in the second-line treatment of NSCLC patients. An EGFR mutation is a promising indication for this combination treatment. More data are required to confirm this strategy in first-line therapy.The effect of combined epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor pathway inhibitors on progression-free survival and overall survival in patients with non–small-cell lung cancer remains controversial. Our analysis showed that epidermal growth factor receptor tyrosine kinase inhibitors plus anti-VEGF/VEGF receptor therapy significantly prolonged progression-free survival in the second-line treatment of non–small-cell lung cancer. Epidermal growth factor receptor mutation is a promising indication for this combination treatment.