SUMMARY The effects of ara-cytidine (ara-C) on the graft-versus-host reaction (GVHR) have been studied. The immunosuppressive activity of ara-C in the GVHR was extremely dependent upon timing of injection. Injections of ara-C on day 3 in the host undergoing a GVHR were most effective in inhibiting GVHR splenomegaly. This indicates that in the mouse strains employed (C57BLC3BF1), the donor cells were proliferating most rapidly on day 3. The immunocompetence of donor cells to elicit a GVHR was not affected by a 5-day course of ara-G injection. The data reported here and in a companion report suggest that (1) the immunosuppressive half-life of ara-C in the mouse is extremely short, (2) ara-C injections are immunosuppressive only during phases of immunocyte proliferation initiated by antigenic stimulation, and (3) ara-C would be very useful for dissection of immune responses into rapid and slow periods of immunocyte proliferation.