MRL/Mp-+/+ (+/+) and MRL/Mp-lpr/lpr (lpr) mice spontaneously produce the SLE-specific anti-nuclear antibody, anti-Sm. Previous work on the clonality and specificity of the anti-Sm response has suggested that the Sm antigen itself induces this autoantibody. In the present work, we have directly investigated the immunogenicity of Sm. In short-term cultures, Sm antigen was shown to be important for the de novo generation of anti-Sm PFC in vitro. The addition of purified Sm to cultures of spleen cells from anti-Sm-positive lpr mice augmented the number of anti-Sm PFC on day 4. Also, the addition of Fab anti-Sm to such cultures inhibited the generation of anti-Sm PFC, probably by blocking determinants on endogenous Sm. The ability of the autoantigen to initiate anti-Sm generation in vivo was investigated by hyperimmunizing +/+ mice with Sm from rabbit or mouse sources. Such mice specifically produced antibodies that recognized both rabbit and mouse Sm as determined by ELISA. The IgG subclass distribution of these induced antibodies was similar to that of spontaneous anti-Sm antibodies found in older mice of the same strain. Our data indicate that the Sm antigen can both initiate and augment production of the anti-Sm autoantibody. These findings provide additional evidence that the spontaneous anti-Sm response in SLE is antigen driven.