Immunoregulatory influences of human anti-immunoglobulins (anti-Ig) were studied in cultures of peripheral blood lymphocytes (PBL) from 11 normal donors. Pokeweed mitogen (PWM)-stimulated PBL released anti-Ig specific for Fab or Fc fragments of IgG, often within the first 24 to 72 hr in vitro. PBL that released more than 1 ng/ml IgM anti-Fab during the first 72 hr in vitro ultimately produced significantly less antibody (Ab) by the 12th day than PBL that released no detectable IgM anti-Fab during the first 3 days in culture. Adding affinity-purified human anti-Fab to PWM-stimulated PBL also suppressed the later Ab release by these cells. Suppression was polyclonal, affecting IgM anti-Fc, IgM anti-Fab, and IgM anti-tetanus toxoid Ab, and was directly dependent on the quantity of anti-Fab added. Anti-Fab Ab, isolated from single donor sera, were more suppressive, nanogram for nanogram, than were equal quantities of IgG anti-Fab obtained from Cohn Fraction II, when added to autologous donor PBL in vitro. Affinity-purified IgM anti-Fc, from pooled rheumatoid arthritis patient sera, also suppressed Ab release by PWM-stimulated PBL in a dose-dependent manner. These observations suggest that anti-Ig may exert a significant immunoregulatory role in man that can override to some extent the T cell-dependent stimulus for polyclonal B cell activation provided by PWM.