It has previously been demonstrated that the expression of the RUNX2 gene is increased in osteosarcoma tissues or cell lines; however, there is little research available on the effect of RUNX2 on osteosarcoma invasion. In the present study, small interfering (si)RNA to RUNX2 was designed and synthesized, and then transfected into SAOS-2 cells. The effects of RUNX2 RNA interference on the invasion of osteosarcoma cells were detected by the soft agar colony forming test and Transwell chamber assay. The expression of the associated proteins, vascular endothelial growth factor (VEGF), matrix metalloprotein-2 (MMP-2) and MMP-9, was detected by western blot analysis. The results revealed that the number of cell colonies was reduced dose-dependently by the siRNA and that the number of cells permeating through the filter membrane was decreased following transfection with the siRNA. The inhibition of RUNX2 caused a notable decrease in VEGF, MMP-2 and MMP-9 expression (0.16 +/- 0.04, 0.16 +/- 0.02 and 0.12 +/- 0.02) compared with the empty vector (0.86 +/- 0.22, 0.74 +/- 0.16 and 0.81 +/- 0.16) and blank control (0.78 +/- 0.12, 0.82 +/- 0.18 and 0.78 +/- 0.14) groups, respectively (P<0.01). It can therefore be concluded that RUNX2 siRNA inhibits the invasion of osteosarcoma cells by inhibiting the expression of VEGF, MMP-2 and MMP-9.