The cellular basis for prostaglandin E2 (PGE2)-mediated suppression of human T-cell proliferative responses was examined. Proliferation in response to concanavalin A was found to be more sensitive to the suppressive influence of PGE2 than was that to phytohemagglutinin. Studies of separated T cells indicated that T4+ cells were inhibited to a greater extent than were T8+ cells. Addition of interleukin 2 (IL-2) to the cultures did not overcome the suppression. In studies conducted in the autologous mixed-lymphocyte reaction (AMLR), both the T4+ cells and the T8+ cells were inhibited by PGE2, however, the T8+ cells were much more prominently inhibited. The inhibitory effect of PGE2 on the responsiveness of T8+ cells was found to be due to inhibition of T4+-dependent IL-2 production. In contrast to the case of mitogen-induced proliferation, the suppression of the AMLR by PGE2 was overcome by addition of IL-2. These results help explain the previously reported suppression of the (B + null) cell induced AMLR by macrophages (which produce PGE). Moreover, they indicate that the effects of the macrophage product, PGE2, can be differentially observed in functional activities of T-cell subsets.