The role of TGF‐β1 in the regulation of T cell responses has been perplexing, possibly because it is dependent on the type of T cell being regulated and its cytokine microenvironment. In the present study, we demonstrate that TGF‐β1 has a profound inhibitory effect on naive CD4⁺ T cell undergoing differentiation under defined neutral, Th1 and Th2 priming conditions. In addition, we show that if CD4⁺ T cells are primed in the presence of TGF‐β1, they exhibit reduced secondary anti‐CD3/anti‐CD28‐induced and antigen‐specific immune responses (even when TGF‐β is absent during the secondary response), which is not due to reduced expression of co‐stimulatory molecules or to inadequate IL‐2 production. Finally, with respect to the effect of TGF‐β on fully differentiated antigen‐specific memory CD4⁺ T cells, we demonstrate that while antigen‐specific activation and cytokine secretion by memory Th1 T cells is inhibited by TGF‐β1, such inhibition is associated with partial down‐regulation of IL‐12 receptor β2 chain expression. In contrast, memory Th2 T cells are not subject to TGF‐β1‐mediated suppression. In summary, these studies reveal that TGF‐β1 is a powerful negative regulator of the primary immune response of CD4⁺ T cells, but only Th1 T cells are subject to such regulation after the memory stage of T cell differentiation has been reached. Thus, these studies define the potential regulatory role of TGF‐β1 in Th1 and Th2 T cell‐mediated autoimmunity.