The ability of interferons to modulate the antigenic phenotype of tumor cells may involve alterations in the transcription, translation, membrane expression and shedding of Major Histocompatibility Complex (MHC) and Tumor Associated Antigens (TAAs). In the present study we have investigated possible mechanisms by which recombinant human interferons, IFN-alpha, -beta and -gamma, alter the antigenic profile of long- and short-term human melanoma cultures. IFN-alpha and -beta induced similar changes in the synthesis, expression and shedding of two TAAs, a HMW-MAA and a Cyt-MAA, in the established melanoma cell line Colo 38, whereas IFN-gamma exerted a differential effect on these melanoma associated antigens. Moreover, IFN-gamma was relatively more effective than IFN-alpha or -beta in upregulating the synthesis, expression and shedding of class I MHC antigens. At the same time a dramatic differential effect of the interferons was observed with class II MHC antigens. IFN-alpha or -beta induced a modest increase in the synthesis and expression of these antigens, whereas IFN-gamma was greater than 3-fold more active in inducing the synthesis and expression of DR/DP antigens and greater than 4- and greater than 10-fold more effective in increasing the synthesis and expression, respectively, of DQ antigens. Analysis of the levels of cytoplasmic mRNA for the DR-alpha and DQ-beta genes indicated no significant difference between IFN-alpha, beta or -gamma treated cells suggesting that IFN-gamma enhancement of the synthesis of DR and DQ antigens may occur at a posttranscriptional level. In the case of a newly established human melanoma cell line (MG-3) IFN-gamma enhanced the synthesis but not the expression of DR antigens and did not alter either the synthesis or expression of DQ antigens. Our studies indicate that the effects of interferons on the antigenic phenotype of melanoma cells will vary depending on the type of interferon employed, the antigen monitored and the target cell studied. In addition, it is also apparent that some of the biosynthetic steps involved in regulating the synthesis, expression and shedding of antigens may be coordinately regulated in some melanoma cells, whereas these processes may be under independent control in other melanoma populations.