Abstract Keyhole limpet hemocyanin was injected into the hind foot pads of rabbits. Six days later popliteal lymph node cell populations were prepared and induced in vitro with various amounts of KLH to produce an anamnestic antibody response. Previously it was observed that cholera enterotoxin which stimulates adenylate cyclase, or dibutyryl cyclic AMP, added for 0 to 24 hr to these cultures with 1 μg or more of KLH, enhanced antibody synthesis many-fold. In the current experiments these observations were confirmed. Moreover, the addition of optimal concentrations of prostaglandins E1 and E2—but not prostaglandin F1α—with 1 μg or more of KLH for 0 to 24 hr enhanced the ensuing antibody response two- to six-fold. When KLH was added for 0 to 24 hr and PGE1 or PGE2 for 72 to 120 hr, the antibody response was inhibited. Enhancement of antibody production required that the KLH-primed LNC first be exposed to KLH (1 to 100 μg) before addition of these PG's. The PG mediated elevation of antibody synthesis was Ca 2+-dependent, whereas the induction of antibody synthesis by KLH was not. The LNC were fractionated on nylon fiber columns. The effluent cells—which consisted of approximately equal numbers of Ig + (B) and Ig − (T) lymphocytes—were induced to produce antibody to the same extent as the unfractionated LNC. However, in contrast to the unfractionated cells, the antibody response of the effluent LNC was not enhanced by added PG. Elevation of the anamnestic antibody synthesis by PG showed the same requirements and specificity as regulation by CT and DbcAMP. Moreover, the magnitude of elevation of antibody synthesis by these different agents was approximately equal. Therefore, it was postulated that these three types of molecules modulate the antibody response via a common pathway involving cyclic AMP. A model is proposed in which KLH elevates cyclic AMP levels in a KLH-regulatory cell population causing production of soluble regulatory factor(s) which then enhance the antibody response by antigen induced T helper and /or B LNC. An antigen-induced elevation of PG may be required for the increase in cAMP, but the increase in cAMP is the crucial regulatory step.