Vascular endothelial growth factor (VEGF) plays important roles in the regulation of angiogenesis and inflammation in both pathological and physiological wound repair. Several strategies have been developed for keloid therapy; however, a universally effective treatment has not been explored to date. In this study, three potential short interfering RNA (siRNA) sequences for the VEGF gene were cloned into expression plasmids and transfected into keloid fibroblasts. PGC-VEGF shRNA 2 (short hairpin RNA 2) plasmid significantly inhibited VEGF expression determined by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and fibroblasts growth was also significantly by (methyl thiazolyl tetrazolium) MTT assay and apoptosis detection, whereas the control transfection showed no obviously effects. Plasminogen activator inhibitor-1 (PAI-1) expression in pGC-VEGF shRNA2 group was also obviously downregulated when compared to the pGC-VEGF shRNA negative control and mock group. These results suggest that modulation of VEGF production by vector-based RNAi in keloid fibroblasts may be a therapeutic potential strategy for keloid.