The expression of human histocompatibility leukocyte antigen class II antigens on gastric epithelia and gastric carcinoma (GaCa) was studied with the use of murine monoclonal antibodies to DR, DQ, and DP antigens. DR and DP antigens but not DQ antigens were demonstrated in fundic glands of normal gastric epithelia, and DP⁺ cells were located in part of the DR⁺ epithelia. Of 15 GaCas examined, 11 expressed DR antigen, and the degree of the expression varied considerably among the specimens. DP antigen was found in 3 of the 11 DR⁺ carcinomas, and the DQ antigen was found in one of the 3 DR⁺ DP⁺ specimens. Thus the expression of class II antigens in normal gastric epithelia and GaCas appears to be in the order of DR, DP, and DQ. Studies on 3 GaCa cell lines (Kato III, MKN28, and MKN45) demonstrated that 1 line (Kato III) expressed DR antigen only, and the remaining lines were negative. Interferon (IFN)-γ treatment enhanced the expression of DR antigen on Kato III cells and induced expression of DQ and DP antigens. The IFN-γ treatment also induced expression of DR antigen but not DQ or DP antigens in 1 of the 2 negative cell lines. The induction of the class II antigens by IFN-γ was shown to be dose dependent. However, maximal induction of DQ and DP antigens on the Kato III cells and DR antigens on MKN45 cells required 10 times more IFN-γ than that needed for the maximal expression of DR antigen on Kato III. Northern blot analyses of cytoplasmic RNA from these cells were in agreement with and affirmed the above-described expression of the class II antigens on the cell lines. The DR antigen on the Kato III cells was capable of stimulating allogeneic lymphocytes in MLR, and its stimulatory activity was significantly enhanced by IFN-γ. These results demonstrated a differential expression of class II antigens in the “DR, DP, and DQ order” in normal gastric epithelia, GaCa cells, and GaCa cell lines, suggesting different mechanisms acting discordantly on the expression of each of these antigens and that the DR antigen on the GaCa cell lines possesses MLR-stimulatory ability.