Prostaglandin E₂ (PGE₂) favors T helper type 2 (Th2)‐like cytokine secretion profiles in murine and human CD4⁺ T cells by inhibiting the production of the Th1‐associated cytokines interleukin‐2 (IL‐2) and interferon‐γ (IFN‐γ) and up‐regulating the production of the Th2‐associated cytokines IL‐4 and IL‐5 in a dose‐dependent way. However, the potent inhibition of IL‐2 production by PGE₂ seems to be in contrast with the simultaneous up‐regulation of IL‐4 and IL‐5 production, because the induction of these cytokines requires IL‐2. We, therefore, investigated to which extent the net modulatory effect of PGE₂ is determined by the availability of IL‐2. To this aim, we examined the effects of PGE₂ on the cytokine secretion profiles of a panel of human Th0 clones upon stimulation via different activation pathways, resulting either in high or low IL‐2 production. The differential modulation of Th1 and Th2 cytokines by PGE₂ was observed only upon modes of stimulation resulting in high IL‐2 production. When IL‐2 production was low, PGE₂ inhibited the secretion of all four cytokines. These different modulation patterns were directly related to the IL‐2 availability, because (i) neutralizing antibody to IL‐2 abrogated the up‐regulatory effect of PGE₂ on IL‐4 and IL‐5 secretion in experiments with high endogenous IL‐2 levels, (ii) lack of differential cytokine modulation by PGE₂ in conditions with low levels of endogenous IL‐2 could be restored with exogenous IL‐2, and (iii) cell viability was comparable in all conditions. These results demonstrate that the net modulatory effect of PGE₂ on the cytokine secretion profile of T cells critically depends on the availability of IL‐2. Since this parameter varies with the experimental conditions and the T cell population studied, this finding may explain why certain immune responses may be either up‐ or down‐regulated by PGE₂ under different conditions.