It has previously been demonstrated that retinoic acid (RA) enhances the blastogenic responses of human thymocytes. We have now delineated the cellular mechanism of this activity. When RA was added to resting thymocyte cultures in the presence of recombinant interleukin-2 (rIL-2), blastogenesis was increased two- to fourfold. By assessing the proportion of cells that became Tac-positive and showed DNA synthesis early in the activation process, we determined that the augmentation by RA was not caused by an increased recruitment of resting cells that are activated to undergo blast transformation. Instead, RA markedly potentiated the growth rate of long-term rIL-2-dependent thymocyte blasts and, correspondingly, increased the Tac expression on these proliferating cells. Thus, RA enhancement of thymocyte responses appears to be mediated by an increase in IL-2-receptor expression on thymocyte blasts, resulting in augmented IL-2-dependent growth. This effect is independent of the original activating stimulus since enhancement of thymocyte responses to phytohemagglutinin (PHA) was also shown to be caused solely by increased proliferation of IL-2-dependent blast growth. In contrast to these effects on thymocytes, peripheral blood lymphocyte (PBL) proliferative responses were unaffected by RA treatment and, correspondingly, RA affected neither IL-2 receptor expression on PBL blasts nor the growth of these cells. Taken together, the results of this study suggest that RA can modulate IL-2-dependent immune responses, in part, by upregulating the expression of IL-2 receptors on proliferating T lymphoblasts generated from cells at restricted stages of development.