We investigated the in vitro effects of human recombinant interferon alpha (rIFN alpha) and interferon gamma (rIFN gamma) on the proliferation and MCH class II antigen expression of two human osteosarcoma cell lines SAOS-2 and U2-OS. Addition of low concentrations of either rIFN alpha (10 U/mL) or rIFN gamma (100 U/mL) to the cultures almost completely inhibited the 3H-thymidine incorporation in SAOS-2 cells while even high amounts (10,000 U/mL) of rIFN alpha or rIFN gamma did not affect the growth rate of U2-OS cells. This difference was not caused by lack of IFN receptors in U2-OS cells since both cell lines responded to rIFN gamma treatment with rapid accumulation of HLA class II mRNA and de novo surface expression of HLA-DR, -DP and -DQ antigens. The induced HLA class II antigens were functionally intact. Osteosarcoma cells treated with rIFN gamma stimulated a mixed lymphocyte culture (MLC) response in allogeneic T-lymphocytes while untreated osteosarcoma cells were unable to provoke T-lymphocyte proliferation. These findings indicate that IFNs display divergent effects on two phenotypically closely related tumor cell lines. This should be appreciated also when therapeutic effects of IFNs are evaluated.