Colon carcinoma is one of the common malignant tumors and has high morbidity and mortality in the world. Pigment epithelial-derived factor (PEDF) has been found to be the most potent natural inhibitor of angiogenesis and PEDF gene has been extensively used for the therapy of tumors, which suggests a potential approach to the therapy of colon carcinoma. However, the transfer of PEDF gene largely depends on the effective gene delivery systems. Poly (lactic-co-glycolic acid) nanoparticles (PLGANPs) have been extensively used for gene therapy due to its low-toxicity, biocompatibility and biodegradability, due to its potential to be an excellent carrier of the PEDF gene. We investigated the effect of PEDF gene loaded in PLGA nanoparticles (PEDF-PLGANPs) on the mouse colon carcinoma cells (CT26s) in vitro and in vivo. Blank PLGANPs (bPLGANPs) showed lower cytotoxicity than PEI to the CT26s. In vitro, PEDF-PLGANPs directly induced CT26 apoptosis and inhibit human umbilical vein endothelial cell (HUVEC) proliferation. In vivo, PEDF-PLGANPs inhibited CT26 tumors growth by inducing CT26 apoptosis, decreasing MVD and inhibiting angiogenesis. Our present study demonstrates the inhibitory effect of PEDF-PLGANPs on the growth of CT26s in vitro and in vivo for the first time. PLGANP-mediated PEDF gene could provide an innovative strategy for the therapy of colon carcinoma.