The relapse and resistance to chemo- and radiotherapy are main problems in the treatment of human liposarcoma. It is important to find a functional marker existing in the liposarcoma cells for targeting. In this article, we established a new sub-cell line SW872-S cells with high tumorigenicity from human liposarcoma SW872 cells by repeated inoculation approach. The characteristic of the sub-cell line is linked to the high levels of integrin α6 on the surface. The integrin α6(high) cells show much higher tumor initiation and self-renewal potential in vivo than integrin α6(low) cells do. Targeting integrin α6 with its specific short interfering RNA and antibody significantly inhibits the cell adhesion to laminin and the tumor growth in vitro and in vivo, respectively. Interestingly, integrin α6 marks almost all of the surgical biopsy specimens of patients with liposarcoma relapse. Moreover, integrin α6 is found to coexpress with CD13, which might contribute to the antiapoptosis ability of integrin α6(high) cells. Consistently, integrin α6(high) cells are more sensitive to the CD13 inhibitor bestatin, and 61% of 23 other human tumor cell lines also contain integrin α6(high) CD13(high) subgroup. These results provide evidence, for the first time, to our knowledge, that integrin α6 and CD13 can serve as functional markers of the tumor-initiation subcell population in human liposarcoma as well as other cancers for therapeutic targeting.