Interleukin (IL-) 2 and IL-15 share the IL-2 receptor βγ_c subunits (IL-2Rβγ_c) but have specific, unique α receptor subunits. We studied species specificity of human (hu), simian (si), and mouse (mu) IL-15 and found that hu and si IL-15 behaved similarly in all systems investigated. Hu and mu IL-15 bound hu or mu IL-15Rα with equal high affinity in the presence or absence of IL-2Rβγ_c and exhibited similar proliferative activities on cells containing all three subunits. However, quantitative differences were noted in the specific activity of hu and mu IL-15 in both in vitro and in vivo systems utilizing IL-2Rβγ_c in the absence of IL-15Rα. These data show that hu IL-15 may be used in mouse model systems, however care must be taken when comparing the efficacy and toxicity of cytokines across species.