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.