Major Histocompatibility Complex (MHC, HLA in humans) class I antigens play an important role in cellular immunology by presenting antigens to T cells. Downregulation of MHC class I expression is thought to be a mechanism by which tumor cells escape from T cell-mediated lysis. In primary human melanomas and melanoma cell lines, HLA-B expression is frequently downmodulated, correlating with elevated expression of the c-myc oncogene. Transfection experiments have shown that c-myc induces HLA-B downregulation through a -68 to +13 base pairs (bp) core promoter fragment, containing CCAAT and TATA-like (TCTA) boxes. Since (i) c-myc has been reported to activate the human p53 promoter and (ii) p53 is capable of repressing a large array of basal promoters, we investigated whether c-myc-induced HLA-B abrogation is mediated by p53. In this article, it is shown that the HLA-B core promoter is indeed repressed by wild-type p53, making p53 a candidate for mediating c-myc-induced HLA-B downregulation. However, transfection of c-myc into p53-null cell lines still resulted in suppression of the basal HLA-B promoter, demonstrating that c-myc and p53 repress the minimal HLA-B promoter through independent mechanisms.