Interleukin-15 (IL-15) has been shown to have anabolic effects on skeletal muscle in rodent studies conducted in vitro and in vivo. The mechanism of IL-15 action on muscle appears to be distinct from that of the well-characterized muscle anabolic factor insulin-like growth factor-I (IGF-I). IL-15 action has not been investigated in a human culture system nor in detail in primary skeletal myogenic cells. The purpose of this study was to compare the effects of IL-15 and IGF-I in primary human skeletal myogenic cells. Accretion of a major myofibrillar protein, myosin heavy chain (MHC), was used as a measure of muscle anabolism. We found that both growth factors induced increases in MHC accretion in primary human skeletal myogenic cultures; however, IL-15 and IGF-I actions were temporally distinct. IL-15 was more effective at stimulating MHC accretion when added to cultures after differentiation of myoblasts had occurred. In contrast, IGF-I was more effective at stimulating MHC accretion when added to cultures prior to differentiation of myoblasts. These results using a human system support recent findings from rodent models which indicate that the primary mode of IGF-I action on skeletal muscle anabolism is through stimulation of myogenic precursor cells, whereas the primary target of IL-15 action is the differentiated muscle fiber. Further, since clinical and experimental studies have shown IGF-I is not effective in preventing skeletal muscle wasting, the distinct mode of action of IL-15 suggests it may be of potential usefulness in the treatment of muscle wasting disorders.