1. We have investigated the effect of prostaglandin E2 (PGE2) on the T lymphocyte activation pathway. 2. At physiologically attainable concentrations (approximately 0.1 microM), PGE2 effectively inhibited the proliferation of murine antigen-specific "helper" T cell clones stimulated either with specific antigen in the presence of macrophages or with phorbol ester plus calcium ionophore A23187. The inhibition was not reversed by the addition of exogenous Interleukin 2 (IL-2) in either case. 3. PGE2 treatment at the same concentrations did not inhibit IL-2 production by phorbol ester plus calcium ionophore-stimulated T cell clones as assayed by CTLL proliferation. 4. These results suggest that the major target (or targets) of PGE2 inhibition directly on T cells lies in the IL-2 signal transduction pathway rather than in the early activation events leading to T cell activation.