Mutations in the tumor suppressor gene p53 are frequent in human glioblastomas. Similarly cathepsin L, a lysosomal cysteine protease, is overexpressed and secreted by most human tumors including glioblastomas. However, hitherto there is no information on whether or not the mutation(s) in the p53 gene affect(s) expression of this protease. Using human glioblastoma cell lines harboring wild type and mutant p53, we demonstrate here for the first time that only the wild type but not the mutant p53 upregulates cathepsin L expression. By transfection of promoter reporter constructs, site-directed mutagenesis and chip assays we have established that wild type p53 elevates the levels of cathepsin L in these cells. It does so directly by binding to the cathepsin L promoter and also indirectly by inducing the expression of C/EBPα, which is crucial for the transcription of this protease. In view of its role in tumorigenesis, angiogenesis and tumor cell invasion, increased expression of cathepsin L in glioblastoma cells harboring wild type p53 might confer invasive ability and growth advantage to these cells. Therefore, use of cathepsin L inhibitors could prove useful in the management of these tumors.