SUMMARY The immunosuppressive effects of ara-cytidine were studied on the cellular and humoral antibody response of mice. The immunosuppressive activity of ara-cytidine allowed dissection of the slow and rapid phases of antibody-forming cell (AFC) appearance. The cellular and humoral antibody responses both exhibited the same time of greatest sensitivity to ara-cytidine. The antibody-forming cell, hemolysin, and hemagglutinin responses were most susceptible to ara-cytidine inhibition 2 days after sheep red blood cell challenge. Injections of ara-cytidine had little effect except during the period of rapid AFC appearance. A normal but diminished primary antibody response occurred after ara-cytidine injections were stopped, except when multiple daily injections were continued for 11 days. In this case, no antibody could be detected after 22 days, and it was speculated that after 11 days insufficient amounts of antigen were present to initiate a detectable response. In contrast to the primary response, no delayed response was found during ara-cytidine inhibition of a secondary antibody response. The primary and secondary antibody forming cell responses were equally sensitive to ara-cytidine inhibition. IgM and IgG antibody-forming cells (detected -by the indirect plaque technique) were inhibited to the same extent by ara-cytidine injections. The immunosuppressive activity of ara-cytidine was dramatically increased by multiple daily injections which suggests that ara-cytidine has a very short immunosuppressive half-life in the mouse, and which corroborates previous reports describing increased anti-leukemic activity of ara-cytidine using multiple daily injections.