Expression of MHC class I antigens requires the intracellular assembly of HLA-A,B,C H chains and beta 2-microglobulin (beta 2m). We have investigated the expression of free H chain, beta 2m, and their mRNAs in tissue sections of colon carcinomas that were defective for the native two-chain molecule. In all of these tumors, beta 2m protein and mRNA were found to be completely absent from the neoplastic cells, whereas free H chains and their respective mRNAs were present in abundance in the tumor cell cytoplasm. The selective abrogation of beta 2m expression represents a unique mechanism leading to a complete loss of class I antigen surface expression in vivo.