It was the objective of these experiments to study the time-related changes in the responsiveness of the cellular elements of the immune system following contact with single non-H-2 or multiple H-2 histocompatibility antigens. The reactivity of spleen cells from mice that received injections of spleen cells bearing H-1c, H-3c, H-13a, or H-2b cell membrane alloantigens was characterized at intervals following antigen contact. Spleen cells taken from mice not receiving injections showed no in vitro proliferative or cytolytic responsiveness to cells bearing individual non-H-2 antigens; after in vivo antigen contact with single non-H-2 antigens there was an interval of specific cellular unresponsiveness followed by alternating periods of responsiveness and unresponsiveness. The duration of the unresponsiveness immediately following injection correlated with the strength of the injected antigen--specifically, the stronger the antigen, the shorter the period of unresponsiveness. The data indicate fluctuation in the level of helper T lymphocyte activity, as well as cytotoxic T lymphocyte activity. In contrast, in vitro responsiveness elicited by H-2b antigens with and without prior in vivo antigen contact was of a similar magnitude, and both persisted at a relatively constant level. Suppressor mechanisms were not studied. Of particular interest was the observation that in vivo contact with non-H-2 antigens resulted in suppression of spleen cell production of IL-2 in response to lectin stimulation and fluctuation in the magnitude of the primary response of cytotoxic T lymphocytes to H-2 antigens.