A proliferation-inducing ligand (APRIL) is overexpressed in most tumor cells and tissues, especially in tumors of the alimentary system, such as colorectal cancer (CRC), gastric cancer, and liver cancer. RNA interference (RNAi) has been proved to be a powerful tool for gene knockdown and holds great promise for the treatment of cancer. In this study, the efficacy of RNAi targeting APRIL was analyzed via relevant experiments on human CRC xenografted in BALB/c nude mice. Both the mRNA and protein levels of APRIL were examined after intratumoral injection of APRIL small interfering RNA (siRNA). Meanwhile, pathological tools were utilized to observe the alterations on the aspects of proliferation, metastasis, apoptosis and cellular necrosis by means of detecting proliferating cell nuclear antigen, Ki-67, MMP-2, MMP-9, TIMP-3, TIMP-4, Bcl-2, Bax and Bcl-xL of CRC. In addition, terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) and hematoxylin and eosin staining were also conducted to examine cell apoptosis and necrosis. It was found that grafted human colorectal tumor growth and metastasis were obviously inhibited while tumor cell apoptosis and necrosis were induced after in vivo APRIL siRNA injection into nude mice. The data indicated that silencing of the APRIL gene using RNAi may serve as a novel therapeutic strategy for treatment of CRC.