Interleukin-2 (IL-2) is a central T cell cytokine that promotes T cell proliferation and effector function; however, toxicity due to its pluripotency limits its application to enhance CAR T cell immunotherapy. Previously, mouse IL-2 and its cognate receptor were engineered to create an orthogonal (ortho) cytokine-cytokine receptor pair capable of delivering an IL-2 signal without toxicity. Here, we engineered a human orthogonal IL-2 (ortho-hIL-2) and human orthogonal IL-2Rβ (ortho-hIL-2Rβ) pair, containing human-specific mutations. Ortho-hIL-2 is selective toward ortho-hIL-2Rβ–expressing cells with no appreciable signaling on wild-type T cells. Ortho-hIL-2 induces IL-2 receptor signaling and supports proliferation of both an IL-2–dependent cell line and primary T cells transduced to express the ortho-hIL-2Rβ. Using CD19-specific chimeric antigen receptor (CAR) T cells, we show that ortho-hIL-2 induces a dose-dependent increase in ortho-hIL-2Rβ⁺ CAR T cell expansion in vivo by as much as 1000-fold at 2 weeks after adoptive transfer into immunodeficient mice bearing CD19⁺ Nalm6 leukemia xenografts. Ortho-hIL-2 can rescue the antileukemic effect of an otherwise suboptimal CAR T cell dose. In addition, ortho-hIL-2 administration initiated at the time of leukemic relapse after CAR T cell therapy can rescue an otherwise failed antileukemic response. These data highlight the potential of combining an orthogonal cytokine approach with T cell–based immunotherapies to augment the antitumor efficacy of engineered T cells.