Perlecan is a major heparan sulfate proteoglycan of basement membranes and cell surfaces. Because of its strategic location and ability to store and protect growth factors, perlecan has been implicated in the control of tumor cell growth and metastatic behavior. To test the role of perlecan in malignancy, we generated several stably transfected clones of HT-1080, a human fibrosarcoma cell line, harboring a perlecan cDNA in the antisense orientation. Surprisingly, clones with a reduced synthesis of perlecan mRNA and protein core grew faster, formed larger colonies in semisolid agar, and induced faster formation of s.c. tumors in nude mice than the wild-type cells. Their growth properties in vitro were independent of exogenous basic fibroblast growth factor. Reduction of perlecan expression was associated with three distinct properties typical of tumor cells with a more aggressive phenotype: enhanced migration through 8-µm-pore filter, increased invasion in Matrigel-coated filters, and heightened adhesiveness to type IV collagen substrata. These results thus provide the first evidence that perlecan may inhibit the growth and invasiveness of fibrosarcoma cells in a basic fibroblast growth factor-independent pathway and raise the possibility that perlecan may prevent the infiltration of host tissues in mesenchymal neoplasms.