Changes in the expression of HLA and beta 2-microglobulin (beta 2-m) antigens by cultured human lymphoid cell lines were investigated. HLA expression was assayed by indirect trace binding radioimmunoassay (RIA) with monoclonal antibodies and by determining sensitivity to complement-dependent lysis by alloantisera. Lymphoid cells in culture were found to undergo changes in the expression of HLA and beta 2-m antigens characterized by decreased membrane expression of these antigens at high cell densities or after a prolonged period of cultivation. The decreased expression of HLA and beta 2-m antigens apparently is due neither to a masking phenomenon nor to a lack of nutrients or an accumulation of metabolites in the culture media but is perhaps mediated by a cell-to-cell contact mechanism. Human interferon was found to enhance the expression of HLA and beta 2-m, apparently overriding the effects on major histocompatibility complex (MHC) expression induced by cell density.