The immunodepressive activity of widely employed steroid contraceptive agents (SCA's) was evaluated in mice and rats on various humoral and cell-mediated responses. Three different progestagens (lynestrenol, norethindrone or norethynodrel) were administered in combination with the estrogen mestrahese SCA's could significantly reduce the severity of allergic encephalomyelitis in rats, variations in their capacity to interfere with primary response to sheep erythrocytes in mice and anti-mouse erythrocyte autoantibody formation were found. Treatments employed with these SCA's did not reduce tumor allograft resistance in mice and the anti-sheep erythrocyte response in rats. In addition, otherwise immunosuppressive treatments with these SCA's did not modify the mouse response to a T-independent antigen. The possible clinical significance of these results is discussed.