Although soluble IL-2 has shown antitumor activity in preclinical studies, clinical use of IL-2 (usually applied systemically) has been limited by its severe toxicity. This necessitates efforts on minimizing toxicity of IL-2-based therapies. Previously, we showed that recombinant immunoregulatory proteins (such as costimulators), after being chemically palmitylated, can be incorporated into cell membranes via the lipid anchorage. Hence, we hypothesized that palmitylation of IL-2 may permit controlled targeting of IL-2, to either antitumor T cells or cells in the tumor microenvironment, thereby bypassing the need to apply IL-2 systemically. In this study, we demonstrated that palmitylated human IL-2 (pal-IL-2) can be incorporated into the surfaces of antitumor T cells, and the pal-IL-2-modified T cells show increases in proliferation and survival in vitro. Subsequently, we showed that pal-IL-2 modification of CD8+ TCR-transgenic OT-1 T cells enhances therapeutic efficacy of the T cells, upon adoptive transfer, against established E.G7-OVA tumors. Also, we showed that intratumoral injection of pal-IL-2 into B16F10 tumor-bearing mice inhibits the growth of tumors and prolongs the survival of treated animals, whereas injection of soluble IL-2 (as control) has minimal efficacy. Collectively, our study suggests that palmitylation of cytokines may provide a novel approach to target cytokines to antitumor T cells or the tumor microenvironment, to minimize the systemic toxicity and, thus, improve the therapeutic efficacy of the cytokines.