Whole anti-I region antisera and monoclonal anti-Ia antibodies are capable of totally inhibiting the response of murine spleen cells to the non-H-2 Mls alloantigens. This inhibition was shown to be highly specific for the appropriate Ia and operative at the level of the stimulator cell. Both cell proliferation and interleukin (IL2) production were inhibited; however, the inhibition of cell proliferation was not due only to the inhibition of IL2 production and the inhibition of IL2 production was not solely due to the inhibition of IL1 production. We propose that both the IL2-producing cell and the proliferating cell need to "see" an intact Ia+ cell and perhaps Ia antigens in association with Mls determinants to respond.