Objective To investigate the effects of siRNA-mediated WISP-2 gene silencing on the proliferation and apoptosis of human glioma cell line U251. Methods Liposome-mediated transfection with WISP-2 siRNA was performed in human glioma U251 cells. The effects of WISP-2 suppression on the proliferation and apoptosis of U251 cells were evaluated by MTT assay and flow cytometry. The protein expression of WISP-2, Bcl-2, and Bax after the gene silencing of WISP-2 in U251 cells was measured by Western blot. Results The MTT assay showed that the cell growth rate was significantly lower in siRNA interference group than in blank control group and negative control group (P<0.05). The flow cytometry showed that the mean apoptotic rate of siRNA interference group was 16.59±1.40%, significantly lower than those of blank control group (3.13±0.34%) and negative control group (3.42±0.48%) (P<0.01). WISP-2 siRNA significantly inhibited the growth and induced the apoptosis of U251 cells. WISP-2 protein expression was significantly lower in siRNA interference group (18.67±1.40%) than in blank control group (70.18±1.82%) and negative control group (69.41±1.77%) (P<0.01). The protein expression of Bcl-2 and Bax was significantly lower in siRNA interference group (29.67±1.47% and 31.62±1.32%) than in blank control group and negative control group (P<0.01). Conclusions WISP-2 siRNA, which inhibits the mRNA and protein expression of WISP-2, can effectively suppress the proliferation and promote the apoptosis of U251 cells. And the cell apoptosis may be induced by down-regulating the Bcl-2/Bax ratio.