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Interleukin-12 (IL-12) is a key cytokine in the development of T helper type 1 (Th1) cell polarization, and its production of IL-12 is redundantly regulated. An important pro-inflammatory cytokine, IL-12 has been shown to have potent immunomodulatory, antitumor, and anti-infection activity in vitro and in vivo. Therefore, following a series of promising results from preclinical animal models experiments, researchers have begun to explore the clinical use of recombinant human IL-12 (rhIL-12) for treating a variety of diseases. In a series of phase I and phase II clinical trials related to cancer, viral infections, and hematopoietic stem cell transplants (HSCT), various strategies of rhIL-12 administration have been used with promising preliminary clinical results associated with tolerable toxicities.