Hindlimb unloading and reloading are characterized by a major loss of muscle force and are associated with classic leukocyte infiltration during recovery from muscle atrophy. Macrophages act as a cellular cornerstone by playing both pro- and anti-inflammatory roles during muscle recovery from atrophy. In the present study, we investigated the role of macrophages in muscle atrophy and regrowth using in vivo and in vitro models. Mice depleted in monocytes/macrophages and submitted to a hindlimb unloading and reloading protocol experienced a significant delay in muscle force recovery compared with matched placebo mice at 7 and 14 days after reloading. Furthermore, an in vitro myotube/macrophage coculture showed that anti-inflammatory macrophages, which contain apoptotic neutrophils and express low levels of cyclooxygenase-2, completely prevented the loss of protein content and the myotube atrophy observed after 2 days in low serum medium. The presence of macrophages also protected against the decrease in myosin heavy chain content in myotubes exposed to low serum medium for 1 day. Interestingly, the addition of an anti-IGF-1 antibody to the coculture significantly decreased the ability of macrophages to protect against myotube atrophy and myosin heavy chain loss after 2 days in low serum medium. These results clearly indicate that macrophages and, more precisely, the release of IGF-1 by macrophages, play an important role in recovery from muscle atrophy.