Abstract C3H HEJ mice repeatedly exposed to rotational stress (45 rpm for 30 min) show a decreased immune response after challenge with sheep erythrocytes (SRBC) or multiple minor histoincompatible skin grafts (B10. BR) in association with the cues present when initially exposed to the physical stress. This conditioned immunosuppression is associated with diminished antibody production and enhanced skin graft survival. When previously conditioned mice were mated with normal (nonconditioned) males and reexposed to conditioning cues during pregnancy (days 13, 16, and 19 of gestation), the offspring of these mice were also found to produce a decreased antibody response (and decreased skin graft rejection response) when tested at 7 weeks of age. This altered immune response in the offspring occurred in the absence of any deliberate direct manipulation of these mice. In a further study a reciprocal crossover design was used to investigate whether altered immunity in the offspring was dependent upon the treatment of the biological mother and/or the fostering mother. The most marked immunosuppression was seen in offspring born to, and fostered on, conditioned mothers reexposed to cues previously associated with physical stress. However, even the offspring of normal C3H HEJ matings developed a reduced immune response if they were fostered on conditioned mothers reexposed to stress-associated cues. These data imply that the developing immune system is regulated by factors in the colostrum/feto-placental unit which are modified by conditioning phenomena.