Comparative studies on the effects of immunosuppressive agents azathioprine (AZ) and 6-mercaptopurine (6-MP) in antibody-mediated immunoregulation are reported. To determine the degree of interference of these agents with the generation of antibody molecules controlling an anti-SRBC response, the donors of mouse anti-SRBC sera were given daily doses of the drugs. Primary antisera from AZ-treated donors were not significantly inhibited by daily doses of 180, 270, and 360 mumol/kg in their ability to suppress the direct PFC response; on the other hand 6-MP was inhibitory at the two higher equimolar dose levels. When the antisera were used in the antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (AD phi) assays, similar differential effects of the two agents were found. Multiple doses of AZ and 6-MP given to the donors of ADCC effector cells enhanced the capacity of these cells to lyse antibody-sensitized SRBC target cells. The enhancement of ADCC with 6-MP was less manifest than that with AZ. When injected before the antigen, AZ acted synergistically with the antibody in the control of the direct PFC response. Possible mechanisms by which AZ can interact with antibody-mediated immune regulation are discussed.